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Liens entre le criblage virtuel (vHTS) de cibles thérapeutiques potentielles et la conception de molécules réelles. Suzanne Sirois Professeure Associée Département de Chimie UQÀM. Champs d’applications in silico. Biologiques Génomique, protéomique, chemogénomique Chimiques - PowerPoint PPT Presentation
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Liens entre le criblage virtuel (vHTS) de cibles thrapeutiques potentielles et la conception de molcules rellesSuzanne SiroisProfesseure AssocieDpartement de ChimieUQM
BiologiquesGnomique, protomique, chemognomiqueChimiques Catalyse, sparations, ractionsDcouvertes dagents thrapeutiques optimisation, dveloppement, biodisponibilitPolymres Gels, adhsifs, lubrifiants, peinturesMatriauxPrdiction de structures, spectroscopieNano-technologieChamps dapplications in silico
PrsentationChimiothques et CibliothquesExemple dapplication: SARS-CoV Mpro Interaction protine-protine: boucle V3 de gp120 VIH-1:CCR5 eProjet denvergure Criblage grande chelle sur cibles thrapeutiques
Projet du Gnome HumainSelon lInternational Human Genome Sequencing Consortium, on estime le nombre de gnes encodant les protines humaines entre 20,000-25,000
Lincoln D. Stein. Human genome: End of the beginning. Nature 431, 915 - 916 2004
LUnivers Chimique10100-400 molcules
Lunion des deux: ChimiognomiqueDcouverte et mise au point de molcules thrapeutiquesIdentification de la fonction des protinesIntgre les informations gnomiquebiologiquechimique pharmacologique et pharmacocintiqueSert comprendre la base molculaire de l'efficacit d'une molcules et prdire sa toxicit potentielle et autres effets indsirablesInteractions protine-protine
Chimiothques (~5M)
Fournisseur
Nombre
Fournisseur
Nombre
ACB
57314
KeyOrganics
34736
ACD
87657
Maybridge
68787
ACDvirt
145824
MaybridgeHTS
50000
Akos
85925
Menai
4512
Aldrich
129080
NCI_DTP
126705
Asinex
274275
NCI_aug2D
250251
Bionet
34681
Otava
86109
ChemDiv
174467
Peakdale
3770
ChembridgeDVS
30000
Pharmacore
10000
ChembridgeEx
280244
Princeton
204215
ChembridgeHTS
50000
Ryan
60350
Chemstar
107028
SPECS
172469
Comgenex
119247
TalonHTS
25169
Enamine
234115
Timtec
109876
Evotec
122998
Toslab
11743
EvotecLeadDisc
76817
Tripos
87467
GandJ
1867
WDI
4413
IBS
195899
WorldMolecules
19401
IFlab
109400
Filtrage: proprits physico-chimiques
Chart5
0.275482847929.31535801218.520060982420.849650349718.174157303420.35014824423.141755039423.88255416195.486666666716.040855910228.768278164221.8601788494
0.094835552214.6445497638.45052615928.513986014MW >50007.885643295617.89864448182.83637400230.00333333332.813661738915.40919732738.5062090438
0.00018252960.01473037020.01041163130.013986014MW 100.01404494380.20670647680.0253932938000.01678499050.07803999980.3258390355
0.00053618080.05571922630.09667943330.0979020979HBdon >50.13342696630.23176180730.00483681790.00285062710.00666666670.03294831470.04727970790.3367003367
0.02031782975.07429230182.41252370512.6818181818RotBond >150.66713483152.1161314578.37132250690.36202964650.060.97042111682.72627327673.3072662105
0.00452901650.54374279490.18889673890.6993006993cycles >60.03511235960.67075207750.40750190450.03135689850.03333333330.19209489110.50355737080.6028022157
0.00420958971.69014986550.68493660060.3041958042SingleChain>70.04213483150.92548127110.03023011160.25655644240.12666666670.11687326710.42209956081.0481155642
0.0110658590.66478801080.34878964790.2727272727ring size >70.09831460670.30170793840.00120920450.04561003420.30333333330.22846237050.20563824760.5403497339
0.00292047412.04431920070.16063659690.3531468531halogene >70.03511235960.325197310700.59578107180.050.08361411930.06322948890.3249339271
0.001562910.76726015110.02528539030.041958042CF3CF2CF20.04915730340.126842610800.00570125430.02333333330.02051498840.00854452550.1321458311
0.102376307711.62482387618.40553303839.3216783217Reactive0.035112359611.89032029064.730407864715.801026225812.15666666679.01820238977.003093118213.3965099019
ACD 87657,0000000
Akos Lithuania 156140,0000
Akos Re-synthetic 134465,0000
Akos OWHp 28600,0000
#REF!
Asinex Pre-formated 14240,0000
Asinex Gold 191576,0000
Asinex Platinum 82699,0000
Bionet 35080,0000
Chembridge DVS 30000,0000
Chembridge Express 321716,0000
Chemical Diversity Clab 175551,0000
Chemical Diversity IDC 110484,0000
Chart6
123.691573970720.462563.023807726836.309767993125.572255264435.565044195934.768858030223.8350294591.638089015327.26644322226.299817184623.6958774758
logP >610.15175950059.272539.199308997318.115684397610.792477093718.81354387718.17184019258.08784145690.766211159811.73374846799.184643510110.8302625518
MW >5009.70240802778.11539.14396169330.04877159412.40073943162.125571162654.67975089031.39260846281.220526904212.56905194813.76965265082.8385536619
Weight >6001.78086534621.584.00345501356.14339760242.010126989219.265266802917.47670693830.16068559190.46809835681.68919507652.96983546620.2216720405
MW 100.29221629520.05250.00251578660.0410228360.15672721430.18355311980.0674807720.0535618640.38233987920.15509459610.06946983550.008636573
HBdon >50.34597306650.5100.00364647430.09885870440.54805576890.07723702820.10712372790.40633183430.13011681470.07038391220.0028788577
RotBond >152.91664943692.8820.52294816644.74315146542.383861115625.448793886822.66378315091.23192287091.04390527773.20296480463.64625228520.356978351
cycles >60.62302719540.710.26667337540.49500888830.81658897282.77022013362.529309419700.25370216281.10657380350.29707495430.0287885767
SingleChain>70.87664888561.29255.19677643880.58708236470.35364089370.05858078290.05691149451.49973219070.17049602091.15362497310.44789762340.2533394749
ring size >70.34045955150.487500.0756643420.221829287900.00569114940.48205677560.10464576130.3520124540.15356489950.043182865
halogene >70.27843250770.3350.07966657440.0756643420.2274553930.07290052980.09674954060.21424745580.00204186850.21318245980.05210237660.6016812529
CF3CF2CF20.08545948260.1325000.066709532200.005691149400.00255233560.10339639740.0127970750.0057577153
Reactive12.155922204311.377.596836817715.779205980214.659218775111.617220146610.922128815113.6582753082.827987891713.64077303337.300731261415.0708198987
#REF!
ChemStar 72549,0000000
ChemStar Plated 40000,0000
Comgenex 119247,0000
Enamine RS 109695,0000
Enamine S 124420,0000
Evotec Lead Discovery 76817,0000
Evotec Screening 122998,0000
G & J 1867,0000
IBS n 195899,0000
IBS S 172153,0000
IFlab 109400,0000
KeyOrganics 34736,0000
Chart7
13.68342604679.833430742318.010035230113.32003546123.048407027319.881818181810.417899846116.916687448414.350132626129.254958820125.40410841524.7535211268
5.32059301064.20075978969.34130457994.898049645412.30860151517.69090909095.4267787385.95062249424.8275862069logP >613.58995994919.80486252231.3204225352
2.10002395461.82641729986.11722002781.994680851110.71831515614.66818181825.05741683445.86813481945.3846153846MW >50017.798271989411.39975026320.088028169
0.31540283730.54792518992.14583110920.22163120574.416268199602.39690619940.97354639450.1856763926Weight >6004.26179242481.59880518080
00.72326125070.170812426600.01611776720.01363636361.328282230416.94450305970.0265251989MW 100.07962635040.18314031780.088028169
0.16369008010.0730566920.66189815310.17730496450.38145382260.29772727272.30456572350.11509908110HBdon >50.21392153830.1674705580.088028169
0.80381145030.81823495033.52300629870.33244680854.0348143771.34318181825.6398721441.73032285292.7055702918RotBond >154.82274223643.36459123962.2007042254
0.07718719220.13150204560.80068324970.02216312060.73604469990.31590909090.80975494260.3059717240.0265251989cycles >61.58064247770.35942511570
0.29677144610.63559322031.35582363620.17730496452.10605490791.06136363642.75442958050.35680715150.2387267905SingleChain>70.95908156350.68506231186.514084507
0.15570519820.23378141441.62271805270.02216312060.46204265840.55454545451.12465964250.16881198570.0265251989ring size >70.34940517930.09744631880.088028169
0.41787548910.86206896551.03555033630.28812056740.34384569920.25681818180.32437551790.09591590090.0530503979halogene >70.10933767510.09989471880
0.00931569560.27030976040.61919504640.13297872340.18804061680.13409090910.11443905130.05754954060CF3CF2CF20.05348038460.06120999930
10.163423917435.359438924623.45468132810.022163120617.1815397846.797727272728.686318614110.240940743211.9098143236Reactive20.750389218411.229341625223.9436619718
Maybridge 75142,0000000
Maybridge Intermediate 13688,0000
MDPI 9367,0000
Menai 4512,0000
Nanosyn Explore 18613,0000
Nanosyn Pharma 44000,0000
NCI DTP 126705,0000
Otava 104258,0000
Peakdale 3770,0000
#REF!
Pharmeks 84143,0000
Princeton 204215,0000
Ryan Intermediate 1136,0000
Chart8
15.93204309798.717280181129.614473400823.606978826720.15383285828.19231282141120.677083333322.747217679241.531124925512.563704005722.2293024852
7.04731989065.627980376713.88470098369.841416563210.714285714311.8572033235logP >6logP >66.39583333339.784993418216.78446734222.84502089498.75447282
6.14719492016.818415726116.060018666110.92463676026.42770719910.5172523758MW >500MW >5005.27083333339.666320954238.388827386511.4399653459.1564139013
1.60772790224.62451542083.20913202671.71870937922.80442485521.6739240095Weight >600Weight >6000.82291666672.078263991410.21033807370.27774946491.6273712073
0.094572229514.84613537340.03589633140.11265490050.39538501430.0011596287MW 100.13541666670.0618293510.119219960800.2842997892
0.99638598984.36378606470.10768899420.2715271960.63736928530.1072656535HBdon >5HBdon >50.26041666670.3041605170.3150813250.00382224030.3823341993
3.85381835389.16154928135.4562423724.26066610826.63944343622.3059216439RotBond >15RotBond >151.63541666672.722485938813.23341565193.04377739271.7597176609
0.59276522441.32423067690.55998276980.41740084921.27257799670.6360563348cycles >6cycles >60.27083333330.74095496431.4136081070.10192640911.1470025979
2.60242510224.60393152422.13224208492.34264421274.22392187360.6951973978SingleChain>7SingleChain>701.08799712790.34914417100.2303808637
0.68564866421.53006964220.76100222560.27441578321.90562613430.5525630693ring size >7ring size >70.093750.54948342570.05960998040.03567424320.2401843047
0.12159286660.6586846890.26563285230.21664403940.44939936050.1072656535halogene >7halogene >700.33407794490.19586136420.16053409440.0735258076
0.04221974530.34649559160.15794385810.10543343250.04753262470.0365283036CF3CF2CF2CF3CF2CF200.11069448320.10218853790.00254816020.039213764
16.176917620825.944286253415.794385813818.026228371719.533748163511.6820993918ReactiveReactive8.6562512.07966013817.542365664718.030781775614.464977207
Ryan Labo 59214
Sigma Aldrich 58298,0000000
Sigma Aldrich L 13929,0000
Sigma Aldrich R 69238,0000
Sigma Aldrich S 46284,0000
SPECS 172469,0000
#REF!
#REF!
Timtec MaxiVerse 9600,0000
Timtec Stock 100276,0000
Toslab 11743,0000
Tripos 78488,0000
World Molecules 20401,0000
Rules1
0.275482847929.31535801218.520060982420.84965034978.174157303420.35014824423.141755039423.88255416195.486666666716.040855910228.768278164221.8601788494
0.094835552214.6445497638.45052615928.51398601407.885643295617.89864448182.83637400230.00333333332.813661738915.40919732738.5062090438
0.00018252960.01473037020.01041163130.0139860140000.0313568985000.0005696350.0054306506
0.00003422430.09991033690.06767560330.08041958040.01404494380.20670647680.0253932938000.01678499050.07803999980.3258390355
0.00053618080.05571922630.09667943330.09790209790.13342696630.23176180730.00483681790.00285062710.00666666670.03294831470.04727970790.3367003367
0.02031782975.07429230182.41252370512.68181818180.66713483152.1161314578.37132250690.36202964650.060.97042111682.72627327673.3072662105
0.00452901650.54374279490.18889673890.69930069930.03511235960.67075207750.40750190450.03135689850.03333333330.19209489110.50355737080.6028022157
0.00420958971.69014986550.68493660060.30419580420.04213483150.92548127110.03023011160.25655644240.12666666670.11687326710.42209956081.0481155642
0.0110658590.66478801080.34878964790.27272727270.09831460670.30170793840.00120920450.04561003420.30333333330.22846237050.20563824760.5403497339
0.00292047412.04431920070.16063659690.35314685310.03511235960.325197310700.59578107180.050.08361411930.06322948890.3249339271
0.001562910.76726015110.02528539030.0419580420.04915730340.126842610800.00570125430.02333333330.02051498840.00854452550.1321458311
0.102376307711.62482387618.40553303839.32167832170.035112359611.89032029064.730407864715.801026225812.15666666679.01820238977.003093118213.3965099019
ACD 87657,0000000
Akos Lithuania 156140,0000
Akos Re-synthetic 134465,0000
Akos OWHp 28600,0000
Asinex Pre-formated 14240,0000
Asinex Gold 191576,0000
Asinex Platinum 82699,0000
Bionet 35080,0000
Chembridge DVS 30000,0000
Chembridge Express 321716,0000
Chemical Diversity Clab 175551,0000
Chemical Diversity IDC 110484,0000
Filtres
%
Rules2
23.691573970720.462563.023807726836.309767993125.572255264435.565044195934.768858030223.8350294591.638089015327.26644322226.299817184623.6958774758
10.15175950059.272539.199308997318.115684397610.792477093718.81354387718.17184019258.08784145690.766211159811.73374846799.184643510110.8302625518
9.70240802778.11539.14396169330.04877159412.40073943162.125571162654.67975089031.39260846281.220526904212.56905194813.76965265082.8385536619
1.78086534621.584.00345501356.14339760242.010126989219.265266802917.47670693830.16068559190.46809835681.68919507652.96983546620.2216720405
0.024810817510.035000.014467127500000.006970543600.0287885767
0.29221629520.05250.00251578660.0410228360.15672721430.18355311980.0674807720.0535618640.38233987920.15509459610.06946983550.008636573
0.34597306650.5100.00364647430.09885870440.54805576890.07723702820.10712372790.40633183430.13011681470.07038391220.0028788577
2.91664943692.8820.52294816644.74315146542.383861115625.448793886822.66378315091.23192287091.04390527773.20296480463.64625228520.356978351
0.62302719540.710.26667337540.49500888830.81658897282.77022013362.529309419700.25370216281.10657380350.29707495430.0287885767
0.87664888561.29255.19677643880.58708236470.35364089370.05858078290.05691149451.49973219070.17049602091.15362497310.44789762340.2533394749
0.34045955150.487500.0756643420.221829287900.00569114940.48205677560.10464576130.3520124540.15356489950.043182865
0.27843250770.3350.07966657440.0756643420.2274553930.07290052980.09674954060.21424745580.00204186850.21318245980.05210237660.6016812529
0.08545948260.1325000.066709532200.005691149400.00255233560.10339639740.0127970750.0057577153
12.155922204311.377.596836817715.779205980214.659218775111.617220146610.922128815113.6582753082.827987891713.64077303337.300731261415.0708198987
ChemStar 72549,0000000
ChemStar Plated 40000,0000
Comgenex 119247,0000
Enamine RS 109695,0000
Enamine S 124420,0000
Evotec Lead Discovery 76817,0000
Evotec Screening 122998,0000
G & J 1867,0000
IBS n 195899,0000
IBS S 172153,0000
IFlab 109400,0000
KeyOrganics 34736,0000
Druggable Rules
%
Rules3
13.68342604679.833430742318.010035230113.32003546123.048407027319.881818181810.417899846116.916687448414.35013262629.254958820125.40410841524.7535211268
5.32059301064.20075978969.34130457994.898049645412.30860151517.69090909095.4267787385.95062249424.827586206913.58995994919.80486252231.3204225352
2.10002395461.82641729986.11722002781.994680851110.71831515614.66818181825.05741683445.86813481945.384615384617.798271989411.39975026320.088028169
0.31540283730.54792518992.14583110920.22163120574.416268199602.39690619940.97354639450.18567639264.26179242481.59880518080
00.72326125070.170812426600.01611776720.01363636361.328282230416.94450305970.02652519890.0011884530.00636583992.5528169014
0.17566740310.17533606081.088929219600.46741524740.12272727271.51690935640.008632431100.07962635040.18314031780.088028169
0.16369008010.0730566920.66189815310.17730496450.38145382260.29772727272.30456572350.115099081100.21392153830.1674705580.088028169
0.80381145030.81823495033.52300629870.33244680854.0348143771.34318181825.6398721441.73032285292.70557029184.82274223643.36459123962.2007042254
0.07718719220.13150204560.80068324970.02216312060.73604469990.31590909090.80975494260.3059717240.02652519891.58064247770.35942511570
0.29677144610.63559322031.35582363620.17730496452.10605490791.06136363642.75442958050.35680715150.23872679050.95908156350.68506231186.514084507
0.15570519820.23378141441.62271805270.02216312060.46204265840.55454545451.12465964250.16881198570.02652519890.34940517930.09744631880.088028169
0.41787548910.86206896551.03555033630.28812056740.34384569920.25681818180.32437551790.09591590090.05305039790.10933767510.09989471880
0.00931569560.27030976040.61919504640.13297872340.18804061680.13409090910.11443905130.057549540600.05348038460.06120999930
10.163423917435.359438924623.45468132810.022163120617.1815397846.797727272728.686318614110.240940743211.909814323620.750389218411.229341625223.9436619718
Maybridge 75142,0000000
Maybridge Intermediate 13688,0000
MDPI 9367,0000
Menai 4512,0000
Nanosyn Explore 18613,0000
Nanosyn Pharma 44000,0000
NCI DTP 126705,0000
Otava 104258,0000
Peakdale 3770,0000
Pharmeks 84143,0000
Princeton 204215,0000
Ryan Intermediate 1136,0000
Druggable Rules
%
Rules4
15.93204309798.717280181129.614473400823.606978826720.15383285828.192312821420.677083333322.747217679241.531124925512.563704005722.2293024852
7.04731989065.627980376713.88470098369.841416563210.714285714311.85720332356.39583333339.784993418216.78446734222.84502089498.75447282
6.14719492016.818415726116.060018666110.92463676026.42770719910.51725237585.27083333339.666320954238.388827386511.4399653459.1564139013
1.60772790224.62451542083.20913202671.71870937922.80442485521.67392400950.82291666672.078263991410.21033807370.27774946491.6273712073
0.094572229514.84613537340.03589633140.11265490050.39538501430.001159628700.0149587139000.029410323
0.35633465062.91433668390.02153779880.10832201970.23766312330.1333572990.13541666670.0618293510.119219960800.2842997892
0.99638598984.36378606470.10768899420.2715271960.63736928530.10726565350.26041666670.3041605170.3150813250.00382224030.3823341993
3.85381835389.16154928135.4562423724.26066610826.63944343622.30592164391.63541666672.722485938813.23341565193.04377739271.7597176609
0.59276522441.32423067690.55998276980.41740084921.27257799670.63605633480.27083333330.74095496431.4136081070.10192640911.1470025979
2.60242510224.60393152422.13224208492.34264421274.22392187360.695197397801.08799712790.34914417100.2303808637
0.68564866421.53006964220.76100222560.27441578321.90562613430.55256306930.093750.54948342570.05960998040.03567424320.2401843047
0.12159286660.6586846890.26563285230.21664403940.44939936050.107265653500.33407794490.19586136420.16053409440.0735258076
0.04221974530.34649559160.15794385810.10543343250.04753262470.036528303600.11069448320.10218853790.00254816020.039213764
16.176917620825.944286253415.794385813818.026228371719.533748163511.68209939188.6562512.07966013817.542365664718.030781775614.464977207
Ryan Labo 59214
Sigma Aldrich 58298,0000000
Sigma Aldrich L 13929,0000
Sigma Aldrich R 69238,0000
Sigma Aldrich S 46284,0000
SPECS 172469,0000
Timtec MaxiVerse 9600,0000
Timtec Stock 100276,0000
Toslab 11743,0000
Tripos 78488,0000
World Molecules 20401,0000
Druggable Rules
%
Sheet1
Database ScoreACDAkosAkosAkosArrayAsinexDatabase ScoreACDAkosAkosAkosArrayAsinex
LithuaniaResyntheticOWHpPreformatedLithuaniaResyntheticOWHpPreformated
8765715614013446528600133672142408765715614013446528600133672.000000014240.0000
163910103189951111970310906812294172.966.170.768.981.593751986.3343
0.917323327813078049701768219070.917.818.920.615.611.905111012.0527
0.8537914451655411726652380.84.97.43.93.33.98108800.2135
0.79444563160230026710.70.82.00.80.70.13981990.0049
0.69594740955300.60.10.40.20.10.00134660.0000
0.55189916000.50.00.10.00.00.00000000.0000
0.412000000.40.00.00.00.00.00000000.0000
0.30000000.30.00.00.00.00.00000000.0000
0.20000000.20.00.00.00.00.00000000.0000
0.10000000.10.00.00.00.00.00000000.0000
96.494.996.388.797.621117498.6053
Asinex GoldAsinex PlatinumBionetChembridgeChembridgeChembridgeDatabase ScoreAsinex GoldAsinex PlatinumBionetChembridgeChembridgeChembridge
82699DVSExpressCNSDVSExpressCNS
1915763508030000321716191576.082699.035080.030000.0000000321716.0000
11440115941925574260322716991.075.271.872.986.773333384.4531
0.9354501684184043931447630.916.718.321.611.793000012.5224
0.8897457929063744010.83.75.62.10.09866671.0944
0.7228963418107280.70.80.50.40.00000000.1584
0.6636131401140.60.20.00.00.00000000.0213
0.517901090.50.00.00.00.00000000.0014
0.43600020.40.00.00.00.00000000.0002
0.3100000.30.00.00.00.00000000.0000
0.2000000.20.00.00.00.00000000.0000
0.1000000.10.00.00.00.00000000.0000
191576Total Score96.796.396.998.665000098.2512
ChemicalChemicalChemicalChemStarChemStarComgenexChemicalChemicalChemicalChemStarChemStarComgenex
DiversityDiversityDiversityPlatedDiversityDiversityDiversityPlated
CLabIDCAntiGCLabIDCAntiG
1755511104847254940000119247175551.0110484.072549.000000040000.0000119247.0000
0.11267037974355695155926000457771.072.272.277.771.067830065.000038.3884
0.9344472305314871445411138311480.917.718.818.717.930777825.060523.5085
0.812448532021840061989277420.85.73.92.44.41742823.978018.6115
0.717431707301041592114810.70.71.10.31.00442461.03606.7395
0.6188493232722530030.60.10.30.00.27043790.33751.5110
0.51912408552960.50.00.10.00.05858110.06500.0403
0.4339015300.40.00.00.00.00827030.00300.0000
0.30501100.30.00.00.00.00041350.00080.0000
0.20000000.20.00.00.00.00000000.00000.0000
0.10000000.10.00.00.00.00000000.00000.0000
96.396.299.194.758163495.480888.7991
Enamine RSEnamine SEvotecEvotecG & JIBS nEnamineEnamineEvotecEvotecG & JIBS n
Lead DiscoveryScreeningRSSLead DiscoveryScreening
76817
109695124420122998186718915109695.0124420.076817.0122998.00000001867.000018915.0000
1560598467621930428551492108531.051.168.128.534.842030079.914357.3777
0.93397729746275394026128651650.927.921.532.329.459747313.786824.5757
0.816611772417643268026012440.812.15.018.417.43247862.57105.2614
0.726481863824611392236830.71.71.07.56.48335750.86232.5276
0.63963531419167765870.60.20.21.10.81806210.19281.8620
0.5347401102880.50.00.00.00.00447160.00000.7613
0.4111000880.40.00.00.00.00000000.00000.1861
0.30000070.30.00.00.00.00000000.00000.0111
0.20000000.20.00.00.00.00000000.00000.0000
0.10000000.10.00.00.00.00000000.00000.0000
93.095.887.889.040147097.327392.5630
IBS SIFlabKeyOrganicsMaybridgeMaybridgeMDPIIBS SIFlabKeyOrganicsMaybridgeMaybridgeMDPI
IntermediateIntermediate
1721531094003473675142136881721531094003473675142.000000013688.0000
111729880819246284484482316104168.173.970.959.679007760.133065.1649
0.94010820302805010722493724120.921.016.720.912.842085732.461323.1750
0.812001700289812613714520.85.65.12.11.34252482.16833.8604
0.729501147178334852020.71.20.70.40.31114420.43471.5096
0.663710315117541450.60.20.10.00.09342310.23670.9288
0.5110261138250.50.00.00.00.00865030.02920.1334
0.428102250.40.00.00.00.00106470.00580.0214
0.314000010.30.00.00.00.00000000.00000.0032
0.27000000.20.00.00.00.00000000.00000.0000
0.10000000.10.00.00.00.00000000.00000.0000
96.196.594.274.277900595.469094.7966
MenaiNanosynNanosynNCIOtavaPeakdaleMenaiNanosynNanosynNCIOtavaPeakdale
ExplorePharmaDTPExplorePharmaDTP
45121861344000126705104258407745121861344000126705.0000000104258.00004077.0000
13510123913613877841663463279177.866.682.161.434828963.636480.4268
0.99074333602337368334916580.918.121.012.326.542914628.910914.5254
0.87912271399596134541300.81.45.32.53.76370312.65032.5509
0.7104103572982748100.70.21.50.61.64744880.50220.1717
0.661767416481350.60.10.60.10.78039540.07770.0000
0.50689562680.50.00.20.00.22177500.03260.0000
0.4070249120.40.00.00.00.07860780.00460.0000
0.30108520.30.00.00.00.02012550.00060.0000
0.2000920.20.00.00.00.00142060.00040.0000
0.1000000.10.00.00.00.00000000.00000.0000
97.595.197.794.491219895.815797.6748
PharmacophorePharmeksPrincetonRyan IntermediateRyan LaboSigmaPharmacophorePharmeksPrincetonRyan IntermediateRyan LaboSigma
1136AldrichAldrich
1000084143204215592145829810000841432042151136.000000059214.000058298.0000
19286495881469097544217829017192.958.971.966.373239471.229849.7736
0.9685225914215335112909212710.96.224.218.627.808098619.620532.8380
0.82986401176825282736810.80.28.24.61.76056343.81945.0513
0.7026752752693217700.70.02.20.90.36971831.10182.1253
0.60450557028815210.60.00.30.20.00000000.29181.5654
0.50155650667490.50.00.10.00.00000000.05570.6424
0.4034110132410.40.00.00.00.00000000.00880.1654
0.3010001480.30.00.00.00.00000000.00050.0247
0.20000000.20.00.00.00.00000000.00000.0000
0.10000000.10.00.00.00.00000000.00000.0000
99.394.096.296.311619796.128392.1860
SigmaSigmaSigmaSPECSSynthonesTalonSigmaSigmaSigmaSPECSSynthonesTalon
Aldrich LAldrich RAldrich SAldrich LAldrich RAldrich S
139296923846284172469280325169139296923846284172469.00000002803.000025169.0000
187534609430462122704232619615162.866.665.871.145539282.982577.9332
0.9341116539109043604645543950.922.021.521.218.809989014.609315.7158
0.812014564243110890227660.86.95.34.25.05134260.62792.4347
0.742114271596238702880.72.11.42.40.96881180.00000.8010
0.61035487364120600.60.40.51.00.14333010.00000.1430
0.53462137440310.50.10.00.10.01275590.00000.0616
0.4641720130.40.00.00.00.00046390.00000.0207
0.30011010.30.00.00.00.00017390.00000.0012
0.20000000.20.00.00.00.00000000.00000.0000
0.10000000.10.00.00.00.00000000.00000.0000
94.595.394.896.132406498.219897.1111
TimtecTimtecToslabTriposWorld MoleculesTimtecTimtecToslabTriposWorld Molecules
MaxiVerseStock20401MaxiVerseStock20401.0000
9600100276117437848896001002761174378488.0000000
178817258657776414614744182.172.449.281.727143072.2710
0.913542038226461914043640.912.718.320.321.947304019.2520
0.82815349230936958880.82.34.315.73.76618083.4822
0.77215079194823270.70.51.15.50.42987461.1220
0.611342894570.60.10.20.50.00305780.1676
0.517120170.50.00.00.00.00000000.0417
0.40361030.40.00.00.00.00000000.0059
0.3030010.30.00.00.00.00000000.0015
0.2000000.20.00.00.00.00000000.0000
0.1000000.10.00.00.00.00000000.0000
960097.796.391.1107.873560396.3438
PhysicoChemical Properties
Table 1
ACDAkosAkosAkosAsinexAsinexAsinex PlatinumBionetChembridgeChembridgeChemicalChemicalACDAkosAkosAkosAsinexAsinexAsinex PlatinumBionetChembridgeChembridgeChemicalChemicalACDAkosAkosAkosAsinexAsinexAsinex PlatinumBionetChembridgeChembridgeChemicalChemical
LithuaniaRe-syntheticOWHpPre-formatedGoldDVSExpressDiversity ClabDiversity IDCLithuaniaRe-syntheticOWHpPre-formatedGoldDVSExpressDiversity ClabDiversity IDCLithuaniaRe-syntheticOWHpPre-formatedGoldDVSExpressDiversity ClabDiversity IDC
87657156140134465286001424019157682699350803000032171617555111048487657.0000000156140.0000134465.000028600.000014240.0000191576.000082699.000035080.000030000.0000321716.0000175551.0000110484.000087657.000156140.000134465.00028600.00014240.000191576.00082699.00035080.00030000.000321716.000175551.000110484.000
logP >524148457732490359631164389861913883781646516065050324152logP >50.275482829.315418.520120.84978.174220.350123.141823.88265.486716.040928.768321.8602logP >50.6800.6990.6350.6390.3880.6820.0250.0660.0800.0020.0090.026
MW >5008313228661136324350151071480299519052270519398MW >5000.094835614.64458.45058.51400.00007.885617.89862.83640.00332.813715.40928.5062MW >5000.4580.5290.5020.4250.0000.4970.0100.0510.0090.0000.0020.014
MW 100.6670.3330.6670.5650.6670.6120.0000.0000.0000.0000.0000.000
HBdon >54787130281944441210683372HBdon >50.00053620.05570.09670.09790.13340.23180.00480.00290.00670.03290.04730.3367HBdon >50.4260.3390.3380.3690.4390.4660.0000.0000.0000.0000.0000.000
RotBond >15178179233244767954054692312718312247863654RotBond >150.02031785.07432.41252.68180.66712.11618.37130.36200.06000.97042.72633.3073RotBond >150.5060.5420.5090.5190.4210.5130.0030.0240.0010.0000.0010.002
cycles >6397849254200512853371110618884666cycles >60.00452900.54370.18890.69930.03510.67080.40750.03140.03330.19210.50360.6028cycles >60.0050.6100.5730.0080.5000.7090.0010.0010.0000.0000.0000.000
SingleChain>7369263992187617732590383767411158SingleChain>70.00420961.69010.68490.30420.04210.92550.03020.25660.12670.11690.42211.0481SingleChain>70.0000.0000.0000.0000.0000.0000.0010.0000.0010.0000.0000.000
ring size >79701038469781457811691735361597ring size >70.01106590.66480.34880.27270.09830.30170.00120.04560.30330.22850.20560.5403ring size >70.0110.0060.0030.0030.0010.0030.0000.0000.0000.0000.0000.000
halogene >725631922161015623020915269111359halogene >70.00292052.04430.16060.35310.03510.32520.00000.59580.05000.08360.06320.3249halogene >70.0050.0190.0030.0060.0010.0050.0000.0000.0020.0000.0000.000
CF3CF2CF21371198341272430276615146CF3CF2CF20.00156290.76730.02530.04200.04920.12680.00000.00570.02330.02050.00850.1321CF3CF2CF20.0020.0060.0010.0000.0000.0010.0000.0000.0000.0000.0000.000
Reactive897418151247492666522779391255433647290131229414801Reactive0.102376311.624818.40559.32170.035111.89034.730415.801012.15679.01827.003113.3965Reactive0.1020.1080.1020.0030.1840.1180.0140.0130.0530.0040.0050.006
N&O72832482186028044056N&O0.00007990.01790.02380.16780.01400.09710.00000.07980.00000.01370.00000.0507
SlogP>50.201s_logP>50.137s2_logP>50.682
Table 3Weight>5000.078s_MW>5000.039s_MW>5000.497
ChemStarChemStarComgenexEnamine RSEnamine SEvotecEvotecG & JIBS nIBS SIFlabKeyOrganicsChemStarChemStarComgenexEnamine RSEnamine SEvotecEvotecG & JIBS nIBS SIFlabKeyOrganicsWeight100.612
72549400001192471096951244207681712299818671958991721531094003473672549.000000040000.0000119247.0000109695.0000124420.000076817.0000122998.00001867.0000195899.0000172153.0000109400.000034736.0000a_don>50.002HBdon>50.001HBdon>50.466
logP >51718881857515439830318172732042765445320946940287728231logP >523.691574020.462563.023836.309825.572335.565034.768923.83501.638127.266426.299823.6959b_rotN>100.189RotBond_100.097RotBond_100.513
logP >6736537094674419872134281445222351151150120200100483762logP >610.15175959.272539.199318.115710.792518.813518.17188.08780.766211.73379.184610.8303
MW >5007039324646678329621542947723672552623912163815064986MW >5009.70240808.115039.144030.048812.400762.125654.67981.39261.220512.569113.76972.8386Unacceptable groups
Weight >6001292632477467392501147992149639172908324977Weight >6001.78086531.58004.00356.14342.010119.265317.47670.16070.46811.68922.96980.2217===================
MW 100.29221630.05250.00250.04100.15670.18360.06750.05360.38230.15510.06950.0086Single Chain>70.000Single Chain>70.000Single Chain>70.000
HBdon >525120404123421952796224771HBdon >50.34597310.51000.00000.00360.09890.54810.07720.10710.40630.13010.07040.0029nbrofringSize > 70.003nbrofringSize > 70.003nbrofringSize > 70.003
RotBond >15211611522447352032966195492787623204555143989124RotBond >152.91664942.880020.52294.74322.383925.448822.66381.23191.04393.20303.64630.3570CF3CF2CF20.001CF3CF2CF20.001CF3CF2CF20.001
cycles >64522843185431016212831110497190532510cycles >60.62302720.71000.26670.49500.81662.77022.52930.00000.25371.10660.29710.0288nbr_halogene0.005nbr_halogene_70.005nbr_halogene_70.005
SingleChain>76365176197644440457028334198649088SingleChain>70.87664891.29255.19680.58710.35360.05860.05691.49970.17051.15360.44790.2533no N & O0.001no N & O0.001no N & O0.001
ring size >724719508327607920560616815ring size >70.34045960.48750.00000.07570.22180.00000.00570.48210.10460.35200.15360.0432Reactive
halogene >72021349583283561194436757209halogene >70.27843250.33500.07970.07570.22750.07290.09670.21420.00200.21320.05210.60170.118Reactive0.118Reactive0.118
CF3CF2CF2625300830705178142CF3CF2CF20.08545950.13250.00000.00000.06670.00000.00570.00000.00260.10340.01280.0058
Reactive881945489059173091823989241343425555402348379875235Reactive12.155922211.37007.596815.779214.659211.617210.922113.65832.828013.64087.300715.0708
N&O8740770420600027933827N&O0.119919010.19250.00000.00360.16560.00000.00000.00000.01380.05400.03470.0777
Exotics110890012400024303281Exotics0.15162170.22250.00000.00000.09970.00000.00000.00000.01230.17600.02560.0029
Error Atom Type4123001857010124886727Error Atom Type0.05651350.05750.00000.00001.49250.00000.00080.00000.00610.28350.06120.0777
Table 5
MaybridgeMaybridgeMDPI 19367MenaiNanosynNanosynNCIOtavaPeakdalePharmeksPrincetonRyanMaybridgeMaybridgeMDPIMenaiNanosynNanosynNCIOtavaPeakdalePharmeksPrincetonRyan
IntermediateExplorePharmaDTPIntermediateIntermediateExplorePharmaDTPIntermediate
751421368845121861344000126705104258377084143204215113675142.000000013688.00009367.00004512.000018613.000044000.0000126705.0000104258.00003770.000084143.0000204215.00001136.0000
logP >51028213461687601429087481320017637541246165187954logP >513.68342609.833418.010013.320023.048419.881810.417916.916714.350129.255025.40414.7535
logP >639985758752212291338468766204182114352002315logP >65.32059304.20089.34134.898012.30867.69095.42685.95064.827613.59009.80491.3204
MW >500157825057390199520546408611820314976232801MW >5002.10002401.82646.11721.994710.71834.66825.05745.86815.384617.798311.39980.0880
Weight >60023775201108220303710157358632650Weight >6000.31540280.54792.14580.22164.41630.00002.39690.97350.18574.26181.59880.0000
MW 100.17566740.17531.08890.00000.46740.12271.51690.00860.00000.07960.18310.0880
HBdon >5123106287113129201201803421HBdon >50.16369010.07310.66190.17730.38150.29772.30460.11510.00000.21390.16750.0880
RotBond >1560411233015751591714618041024058687125RotBond >150.80381150.81823.52300.33244.03481.34325.63991.73032.70564.82273.36462.2007
cycles >658187511371391026319113307340cycles >60.07718720.13150.80070.02220.73600.31590.80980.30600.02651.58060.35940.0000
SingleChain>722387127839246734903729807139974SingleChain>70.29677140.63561.35580.17732.10611.06142.75440.35680.23870.95910.68516.5141
ring size >711732152186244142517612941991ring size >70.15570520.23381.62270.02220.46200.55451.12470.16880.02650.34940.09740.0880
halogene >73141189713641134111002922040halogene >70.41787550.86211.03560.28810.34380.25680.32440.09590.05310.10930.09990.0000
CF3CF2CF27375863559145600451250CF3CF2CF20.00931570.27030.61920.13300.18800.13410.11440.05750.00000.05350.06120.0000
Reactive76374840219713198299136347106774491746022932272Reactive10.163423935.359423.45470.022217.18156.797728.686310.240911.909820.750411.229323.9437
N&O211419369610114529917790119687N&O0.28080173.06113.93940.13300.05370.25914.182217.06340.02650.02260.03330.6162
Exotics317196021552062781932230Exotics0.04125520.51871.02490.00000.01070.03414.10880.26660.02650.11050.10920.0000
Error Atom Type2581226715560152815521111203Error Atom Type0.34334990.89130.71530.02220.29550.13641.20600.14870.05310.13190.05880.2641
Table 7
Ryan LaboSigmaSigmaSigmaSigmaSPECSTimtecTimtecToslabTriposWorld MoleculesRyan LaboSigmaSigmaSigmaSigmaSPECSTimtecTimtecToslabTriposWorld Molecules
AldrichAldrich LAldrich RAldrich SMaxiVerseStockAldrichAldrich LAldrich RAldrich SMaxiVerseStock
592145829813929692384628417246996001002761174378488204015921458298.000000013929.000069238.000046284.0000172469.00009600.0000100276.000011743.000078488.000020401.0000
logP >594345082412516345932848623198522810487798614535logP >515.98.717280229.614523.607020.153828.192320.677122.747241.531112.563722.2293
logP >641733281193468144959204506149812197122331786logP >67.05.627980413.88479.841410.714311.85726.39589.785016.78452.84508.7545
MW >50036403975223775642975181395069693450889791868MW >5006.16.818415716.060010.92466.427710.51735.27089.666338.388811.44009.1564
Weight >60095226964471190129828877920841199218332Weight >6001.64.62451543.20911.71872.80441.67390.82292.078310.21030.27771.6274
MW 100.42.91433670.02150.10830.23770.13340.13540.06180.11920.00000.2843
HBdon >55902544151882951852530537378HBdon >51.04.36378610.10770.27150.63740.10730.26040.30420.31510.00380.3823
RotBond >1522825341760295030733977157273015542389359RotBond >153.99.16154935.45624.26076.63942.30591.63542.722513.23343.04381.7597
cycles >63517727828958910972674316680234cycles >60.61.32423070.56000.41741.27260.63610.27080.74101.41360.10191.1470
SingleChain>7154126842971622195511990109141047SingleChain>72.64.60393152.13222.34264.22390.69520.00001.08800.34910.00000.2304
ring size >7406892106190882953955172849ring size >70.71.53006960.76100.27441.90560.55260.09380.54950.05960.03570.2402
halogene >7723843715020818503352312615halogene >70.10.65868470.26560.21660.44940.10730.00000.33410.19590.16050.0735
CF3CF2CF2252022273226301111228CF3CF2CF20.00.34649560.15790.10540.04750.03650.00000.11070.10220.00250.0392
Reactive957915125220012481904120148831121132060141522951Reactive16.225.944286315.794418.026219.533711.68218.656312.079717.542418.030814.4650
N&O18393268846027732465862030N&O0.315.99711830.63180.66445.99130.14260.05210.08580.01700.00000.1471
Exotics25778495719419007621328073Exotics0.413.46358370.40920.28024.10510.04410.02080.13160.06810.00000.3578
Error Atom Type1484751316230012302151981923Error Atom Type0.20.81477920.09330.23400.64820.07130.00000.21440.16181.04350.1127
44000126705.000104258.0003770.00084143.000204215.0001136.00059214.00058298.00013929.00069238.00046284.000172469.000
8765715614013446528600142401915768269935080300003217161755511104847254940000119247109695124420.000000076817.0000122998.00001867.0000195899.0000172153.0000109400.000034736.000075142.000013688.00009367.00004512.0000186139600100276117437848820401
2889819
Sheet2
Sheet3
FiltrageGroupes Ractifs
sulfonyl halides
acyl halides
alkyl halides
anhydrides
halopyrimides
-halocarbonyl
1,2-dicarbonyl
aldehydes
Aliphatic ketones
Perhalo ketones
Aliphatic esters
Thio esters
Phosphonate esters
aziridines
Epoxides
imines
Michael acceptors
X = F, Cl, Br, I, tosyl, methyl
R = alkyl, aryl, hetroalkyl, heteroaryl
These reactive functional groups are generally prone to decomposition under hydrolytic conditions. They are reactive toward protein and biological nucleophiles (glutathione, dithiothreitol) and they exhibit poor stability in serum. (Reactive compounds and in vitro false positives in HTS, DDT, 2, 9, 382 (1997))
Tudor I. Oprea, Comp. Aided. Mol. Des. 14, 251-264 (2000)
% de molcules < 2 violation des critres
Chart1
92.660024642985.144023895388.021383285593.209735870496.802282333499.8797.947855949498.706002235494.34678077788.961767196764.508958816587.290006637667.575080871664.398504257295.232992172290.282239913992.416818618894.043642044196.449913024996.752002716197.761528015186.294162750289.360322952395.393045425496.3199.71000051592.579881668192.826845169192.045526504595.395132064892.954784393371.719320297295.21305465762.882394790639.4493.6343479156
ACD
Akos
Aldrich
Asinex
Bionet
ChembridgeDVS
ChembridgeEx
ChembridgeHTS
ChemDiv
ChemStar
Comgenex
Enamine
Evotec
EvotecLeadDis
G&J
IBS
Iflab
KeyOrganics
Maybridge
MaybridgeHTS
Menai
NCI-aug2D
NCI-DTP
Otava
Peakdale
Pharmacophore
Princeton
Ryan
SPECS
TalonHTS
Timtec
Toslab
Tripos
WDI
WDI antibiotics
WorldMolecules
fournisseur
Pourcentage
Sheet1
Sheet1
92.660024642985.144023895388.021383285593.209735870496.802282333499.8797.947855949498.706002235494.34678077788.961767196764.508958816587.290006637667.575080871664.398504257295.232992172290.282239913992.416818618894.043642044196.449913024996.752002716197.761528015186.294162750289.360322952395.393045425496.3199.71000051592.579881668192.826845169192.045526504595.395132064892.954784393371.719320297295.21305465762.882394790639.4493.6343479156
ACD
Akos
Aldrich
Asinex
Bionet
ChembridgeDVS
ChembridgeEx
ChembridgeHTS
ChemDiv
ChemStar
Comgenex
Enamine
Evotec
EvotecLeadDis
G&J
IBS
Iflab
KeyOrganics
Maybridge
MaybridgeHTS
Menai
NCI-aug2D
NCI-DTP
Otava
Peakdale
Pharmacophore
Princeton
Ryan
SPECS
TalonHTS
Timtec
Toslab
Tripos
WDI
WDI antibiotics
WorldMolecules
supplier
Percentage
0 and 1 Flag
Sheet2
Sheet3
Criblage virtuel de cibles potentielles (virtual High Throughput Screening) vHTSStructure 3D cibleSite Fonction de la protineLigand ComplexChimiothquesModle pharmacophoreAlgorithmes, OrdinateursCriblage vHTSListe de touches (hits)
ApplicationCriblage Virtuel sur SARS-CoV Mpro
Donnes du WHO sur le SARSau 31 dcembre 2003 http://www.who.int/csr/sars/country/table2004_04_21/en/index.html
29 pays touchs 8096 cas 774 morts Canada 251 cas 43 morts
Transmission par contact face- face
Projet SRAS: Nos CollaborateursS. Sirois, et al., Virtual Screening for SARS-CoV Protease Based on KZ7088 Pharmacophore Points, J. Chem. Inf. Comput. Sci. 44, 1111-1122, (2003).Q-S. .Du, et al. , Polyprotein Cleavage Mechanism of SARS-CoV MPro and Chemical Modification of the Octapeptide, Peptides 25, 1857-1864 (2004).Dongqing Wei, et al. , Anti-SARS Drug Screening by Molecular Docking, Amino Acids, accepted (2005)Q-S. .Du, et al. , Molecular Modelling and Chemical Modification for Finding Peptide Inhibitor Against SARS-CoV Mpro, Analytical Biochemistry, 337, 262-270 (2005).
Tianjin Institute of Bioinformatics and Drug Discovery (TIBDD) et Tianjin Normal University
Modlisation 3D par HomologieSi la structure 3D de la cible est inconnueConstruire la serrure pour ensuite trouver la cl
Modlisation par Homologie Structure 3D - SARS-CoV Mpro HCov 40%, TGEV 44%304 AA. domaine 1 (res. 899) mauvedomaine 2 (res. 100183) jaunedomaine 3 (res. 200300) bleuBoucle (res. 184199 ) liant les domaines 2 et 3 mauve . Site de liaison localis entre les domaines 1-2K. Anand, et al. Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs. Science 300, 1763-1737 (2003)
Modlisation et Superposition des Structures 3DModlisation 3D de SARS MPro partir de HCoVPDB: 1P9S
ExprimentalePDB: 1UJ1
RMS = 1.4
PeptidomimtiqueDyade Catalytique de SARS-CoV Mpro His-41 et Cys-145
Superposition des ligands naturelsSuperposition des peptides 1UK4-SARS (vert) et 1P9U-TGEV (rouge) partir des coordonnes des structures cristallines Modes de liaisons diffrents pour les ligands du SARS et TGEV MPro
Superposition des ligands naturelsDomaines I et IISuperposition de 6 structures complexes du SARS: 1UK4, 1WOF, 2A5I, 2AMD, 2AMQ, 2D2D Montre une poche de liaison conserve o le sous-site S1 est dans un creux prononc qui contient les rsidus de la diades catalytiques Cys145 and His41.
Superposition des ligands naturelsSurface molculaire de la poche partir des 6 ligands complexs 1UK4, 1WOF, 2A5I, 2AMD, 2AMQ, 2D2D. Bleu: rgion hydrophobe Vert hydrophileRouge: surface expose au solvent
Superposition des ligands naturelsSurface molculaire consensus partir des 6 ligands complexs 1UK4, 1WOF, 2A5I, 2AMD, 2AMQ, 2D2D. Pair dlectrons libre: pourprehydrophobe: vert
Enthalpie, entropie
Comment trouver dautres types dinhibiteurs
Modle Pharmacophore de KZ7088 KZ7088 amarr dans site de liaison de SARS-CoV Mpro
7 points pharmacophores
Criblage Virtuel sur 5M molcules a donn 2789 touches (hits)0.07% satisfait 5 des 6 liaisons hydrognes (points pharmacophore)
Proprits physico- chimiques%Violation17023 117 2 47 >2S. Sirois, et al., Virtual Screening for SARS-CoV Protease Based on KZ7088 Pharmacophore Points, J. Chem. Inf. Comput. Sci. 44, 1111-1122, (2003).
Exemples de touches obtenuesFonction dvaluation
Modification virtuelle Modification
Calcul E int
Convergence?
Principales Cibles anti-VIH-1
gp120/gp41 :CCR5/CXCR4
Modles thoriques: CCR5Superposition de 3 modles CCR5 1OPN, 1OPW et 1OPT
Structure 3D: gp120 (1G9M)
Complexe CCR5 gp120 incluant boucle V3
Servir la conception rationnelle de nouveau inhibiteurs base sur interactions entre le co-receptor CCR5 et la boucle V3.
HIV-1 V3 Loop for Structure-Based Drug Design S. Sirois, T. Sing and K.C.-Chou,Current Protein and Peptide Science, 6(5), 413-422 (2005)
Structure of a V3-Containing HIV-1Gp120 core Huang et al. Science 11 Nov 2005
Superposition des Boucles V3 (RMN)
Structure 3D boucle V3 (RMN)GPG Position 25 Arg + bleuGln - rougePosition 10 Lys + bleu
Improving HIV-treatment: Predicting HIV coreceptor CCR5 and CXCR4 usage through V3 genotype
Modlisation par homologie des structures 3D de la boucle V3Corrlation avec lusage du corcepteur Choix de traitement R5 R5X4 X4Suite du projet
Virus Influenza H5N1Genetic Insight of The H5N1 Influenza Virus High Pathogenicity, Wei et al. soumis Nature Genetics novembre 2005356 gnes HA de H5N1
Criblage virtuel pour H5N1
Projet denvergureScreensaver Lifesaver ProjectComputational Drug Design at the University of OxfordThe National Foundation for Cancer Research Centre United Devices members
Virtual screening using grid computing: the screensaver project W. Graham Richards Nature Reviews Drug Discovery 1, 551-555 [2002].
Le Projet THINKhttp://www.chem.ox.ac.uk/curecancer.html3.5 milliard molcules cribles3.5 millions provenant de chimiothques connues respectant les critres de Lipinski dagents thrapeutiques Chaque molcule est varie 100 fois en ajoutant un substituant alatoirementChimie combinatoire3 semaines pour processer une cible
Combien dannes?Si 25000 cibles potentielles X 3 semaines= 75000/52 = 1442 annes pour 3.5 milliard molcules cribles
Si 1024-40 milliard molcules potentielles Avec une chimiothque de 3.5 milliard molcules On a cribl uniquement 109/10 24 soit 10-15 de toutes les molcules potentielles
Nombre de structures dans PDB
Solution: Calculs sur Rseaux dOrdinateurs (Grid Computing)
Construction de Chimiothques DiversifiesBut: Augmenter la qualitdu criblage en fonction diversit molculaire Proprits ADMET
Processus
Soit une chimiothque relleNombre de Violation0: mauve1 : bleu2: vertn: orange- rougeEnlve les composs non-ADMET
Comment la diversit est-elle dfinie?Comment reprsenter plus de 4 descripteurs?
Une combinaison de tous?
Topologique
2-D formules structuraleslectrostatiqueCharge positive ou ngativeGomtrique3-D forme et structureQuantiqueOrbitales atomiques et molculaires
Types de Descripteurs Molculaires
Exemple avec 25 Descripteurs25 descripteurs DLI (Drug-like Index)Chaque structrure est reprsente par un point dans un espace 25 dimensions
Reprsentation Graphiques 3D:
Soit 2 Chimiothques
Chimiothque assemblee
Nombre de molcules
Hole-Filler
25 DLI
Difference
Assemble (MCT)
125 170
100 706
24 674
MCT
100706
98 214
1492
Chimiothque-2
10 000
9247
753
O se situe le domaine des molcules biodisponibles?
Rsum Mthodes in silico et CHP
`> 10,000,000 composs sont cribls pour trouver une seule drogue1 drogue>1,000 hits6 drogues candidates10-15 ans$300 to >$800 milliontudes pr-cliniques tudes cliniques: Phase I III12 leadsProcessus de dcouverte de mdicaments: temps et cots
Vers la Bio-intelligence
MerciA tous les collaborateursDQ Wei, KC ChouT Sing, R HarriganR. RoyetV. Makarenkov
HCoV 229E ou 3C-like proteinase (3CLpro) Approcher la structure 3D partir de la comparaison de la squence avec les banques de donesRecherche d' homologiesSi la protine tudie partage plus de 30% d'acides amins, aprs alignement , avec une protine connue, on peut supposer que ces deux squences possdent des structures 3D proches
This is primarily achieved by the 33.1-kD HCoV 229E main proteinase (Mpro) (7), which is frequently also called 3C-like proteinase (3CLpro) to indicate a similarity of its cleavage-site specificity to that observed for picornavirus 3C proteinases [3Cpro (table S1)], although we have recently shown that the structural similarities between the two families of proteinases are limited (8). The Mpro (3CLpro) cleaves the polyprotein at no less than 11 conserved sites involving Leu-Gln (Ser,Ala,Gly) sequences (the cleavage site is indicated by ), a process initiated by the enzyme's own autolytic cleavage from pp1a and pp1ab (9, 10). This cleavage pattern appears to be conserved in the Mpro from SARS coronavirus (SARS-CoV), as we deduced from the genomic sequence published recently (11, 12) and prove experimentally here for one cleavage site (see below). The SARS-CoV polyproteins have three noncanonical Mpro cleavage sites with Phe, Met, or Val in the P2 position, but the same cleavage sites are unusual in other coronaviruses as well. The functional importance of Mpro in the viral life cycle makes this proteinase an attractive target for the development of drugs directed against SARS and other coronavirus infections.
The reason to select the octapeptide AVLQSGFR is as follows. (1) The protease-susceptible sites in proteins usually extend to an octapeptide, as generally formulated by P4P3P2P1P1P2P3P4 with the scissile bond located between the subsites P1 and P1, as generally expressed by P1P1 [2, 3 and 4]. (2) The SARS coronavirus enzyme and several viral proteinases exhibit Gln(Ser, Ala, and Gly) specificity [1]. (3) According to the "lock-and-key" mechanism in enzymology, the octapeptide cleavable by the SARS proteinase must have a good fit for binding to the active site. However, such a peptide, after a modification of its scissile bond with some simple routine procedure, will completely lose its cleavability but it can still bind to the active site. Actually, the molecule thus modified can be compared to a "distorted key" that can be inserted into a lock but can neither open the lock nor be pulled out from it, spontaneously becoming an ideal competitive inhibitor against the SARS proteinase. Therefore, it would provide us with useful insights for drug design by studying the binding mechanism of SARS proteinase with octapeptides that are cleavable by the enzyme itself. For a detailed discussion about the rationale of "distorted key," see a review by Chou [5] and Fig. 2 therein.