LUẬN VĂN HOÀN CHỈNH

Lun vn tt nghip i hc

GVHD: TS.Thi Khc Minh, ThS. Tng H

CHNG 1: T VN

SVTH: L Quang Hin - 071933H

1



Trong c th con ngi, c nhiu qu trnh hnh thnh hoc hu hoi t bo thng xuyn din ra. C nhng cht tng nh l ngun cung cp dng cht chnh ca t bo nhng ng thi cng c th lm hi t bo, c nhng cht gy ra nhng tc hi th cng c nhng cht khng li hot ng ny. Trong , gc t do, oxy v cht chng oxy ha l mt th d. Nhng phn t ny c lin h vi nhau v nh hng ti hot ng sng ca c th con ngi rt nhiu, nht l giai on cui ca cuc i. Ngoi ra, mt trong nhiu l thuyt c gng gii thch nguyn nhn s lo ha l tc dng ca nhng gc t do vo cc phn t trong c th. V tr hon tin trnh ny, cc cht chng oxy ha c nghin cu v rt nhiu ngi cao tui hin nay ang dng. Trong qu trnh ho hc, mt in t b tch ri th lp tc phn t tr thnh mt gc t do. Do , gc t do ny khng cn bng, khng n nh v in t nn d to ra phn ng v lun lun tm kim in t t cc phn t khc, v ln lt to ra mt chui nhng gc t do mi, gy ri lon cho sinh hot bnh thng ca t bo. Trong cuc i ca mt ngi sng ti 70 tui, th c chng 17 tn gc t do c to ra nh vy. Nm 1954, bc s Denham Harman thuc i hc Berkeley, California, l nh khoa hc u tin nhn ra s hin hu ca gc t do trong c th vi nguy c gy ra nhng tn thng cho t bo.Trc , ngi ta cho l gc ny ch c ngoi c th. Gc t do c tc dng khng tt cho c th ngay t lc con ngi mi sinh ra v mi t bo chu s tn cng ca hng chc ngn gc t do mi ngy. tui trung nin, c th kho mnh, c th khng tc hi ca chng, nhng khi ln tui, gc t do hot ng mnh m hn v sc khng ca c th gim st, nn gy nh hng gp mi ln so vi tui trung nin. Gc t do ph rch mng t bo khin cho cht dinh dng b mt, t bo khng tng trng, tu b, ri cht. Gc t do cn to ra cht lipofuscin tch t di da to ra nhng vt i mi trn c th, v tiu hy hoc ngn cn s tng hp cc


2



phn t cht m, ng bt, m, enzyme trong t bo. Ngoi ra, cn gy t bin gene, nhim th, DNA, RNA, v lm cht collagen, elastin mt n tnh khin da nhn nheo, c khp cng nhc. Nh quan st thc nghim, gc t do c t cc sinh vt cn nh v c nhiu hn sinh vt sng lu. Mt ngi c nhiu gc t hn khi cao tui v t hn khi ngi cn tr. Theo cc nh khoa hc th gc t do c th l th phm gy ra ti trn 60 bnh, ng k nht gm c: bnh va x ng mch, ung th, Alzheimer, Parkinson, c thu tinh th, bnh tiu ng, cao huyt p khng nguyn nhn, x gan. Gc t do c to ra bng nhiu cch, c th l sn phm ca nhng cng thng thn kinh, th xc bnh hay mt mi, nhim mi trng, thuc l, dc phm, tia phng x mt tri, thc phm c cht mu tng hp, nc c nhiu clo v ngay c oxy. Trong lnh vc y khoa hin nay, vn c cp nhiu nht hin nay l tc hi ca cht oxy ho, phn ng oxy ho v nhn mnh s cn thit s dng cc cht chng oxy ho bo v, duy tr sc kho cho con ngi. Tuy nhin, vic nghin cu v tng hp ra mt loi cht chng oxy ho c thng s chng oxy ho xc nh v c s dng cho con ngi gm nhiu giai on rt phc tp v kh khn, i hi chng ta phi tn nhiu cng sc v kinh ph. Nhng vi s h tr ca my tnh, c th l ho tin hc, cng vic thc s nng n hn, rt ngn thi gian v t tn km hn. Chnh iu ny ang m ra mt hng i mi cho vic tm ra cht chng oxy ho ni ring v trong lnh vc nghin cu v tng hp thuc, cht hu c ni chung. Vi phng php ny, trong tng lai c th thy r c hnh dng cu trc ca cht chng oxy ho nhm phc v cho qu trnh nghin cu sau ny. Trn th gii c nhiu cht chng oxy ho c tm ra v xc nh c ch s chng oxy ho, tuy nhin ti ny, hng nghin cu chnh l hp cht flavonoid. V hp cht ny c s hin din rng ri trong nhiu loi thc vt xung


3



quanh i sng ca ta, tiu biu l h cam. ng thi trn th gii c 4000 loi flavonoid c xc nh cu trc ho hc. y l c s to d liu cho vic thc hin ti: Nhim v chnh l: - Tp hp cc cu trc ha hc ca d n cht flavonoid c hot tnh chng oxy ha t cc ti liu tham kho trong v ngoi nc - Nghin cu xy dng mi quan h gia cu trc ha hc cc d n cht flavonoid v hot tnh chng oxy ha bng cc phn mm ha tin hc thch hp


4



CHNG 2: TNG QUAN


5



2. TNG QUAN 2.1. Tng quan v cht chng oxy ho 2.1.1.Khi nim Cc cht chng oxy ha l nhng cht kh mnh v c hot tnh vi oxy cao hn dc cht m n bo v. Cc cht chng oxy ha l nhng cht m khi hin din nng thp hn so vi dc cht m n bo v c kh nng lm tr hon hay lm gim qu trnh oxy ha ca dc cht . Trong c th c nhiu h thng chng oxy ha ni sinh c kh nng bo v nhng cht ha hc t nhng phn ng oxy ha c hi bng cch phn ng vi cc gc t do hay nhng dng oxy hot ng khc, v vy ngn cn tin trnh oxy ha. Tuy nhin s cung cp cc cht chng oxy ha ni sinh ny c gii hn v th cn c ngun b sung cht chng oxy ha t bn ngoi vo. 2.1.2. C ch tc ng ca cc cht chng oxy ha Cc cht chng oxy ha ng vai tr l cht cho hydro n cc gc t do to thnh cc gc t do mi bn vng hn. C ch phn ng c thu gn nh sau: Cht khi u R + O2 RO2 + RH RO2 + RO2 RO2 + R R + R K6

K1

R RO2

K2K3 K4

ROOH + R sn phm bn sn phm bn sn phm bn

K5

Dng ROOH l dng bn vng v cc sn phm ngt mch l n nh. Ngoi c ch nh trn cc cht chng oxy ha cnc th to phc chelat vi ion kim loi (nh Fe3+, Cu2+, Ni2+, Mn2+), cc ion ny thng khi mo cho phn ng oxy ha.


6



2.1.3. Phng php xc nh hot tnh chng oxy ha Trong cc phng php xc nh hot tnh chng oxy ha, cc phng php nh bt gc t do 1,1-diphenyl-2-picrylhydrazyl (DPPH) v m hnh beta-caroten acid linoleic dng nh gi rt ph hp kho st hot tnh chng oxy ha ca cc flavonoid, do cc flavonoid kho st khng hp thu trong vng hp thu ca DPPH v beta-caroten. Hn na s dng 2 phng php ny rt thun li nghin cu nh gi mang tnh sng lc v hng lot trn i tng m u kh ln. Phng php nh bt gc t do DPPH v m hnh beta-caroten - acid linoleic cng c rt nhiu tc gi p dng nghin cu hot tnh chng oxy ha ca cc flavonoid. 2.1.3.1. Phng php nh bt gc t do DPPH Da vo kh nng bt gi gc t do DPPH ca cht c tc dng chng oxy ha. Nguyn tc: Cc cht nghin cu c tc dng chng oxy ha theo c ch dp tt gc t do s lm gim mu ca dung dch DPPH. Xc nh kh nng ny bng cch o hp thu bc sng c hp thu cc i ti 517 nm. M t: Dng 1 ml dung dch flavonoid (nng 10-4M pha trong methanol) cho vo 2 ml dung dch DPPH ( nng 10 mg/L pha trong methanol). Hn hp c lc u v nhit phng. o hp thu sau 5 pht v 30 pht bc sng 517 nm, mi ln o 3 ln ly gi tr trung bnh. M u i chiu c tin hnh trong cng iu kin nhng khng s dng flavonoid. Kh nng nh bt gc t do c tnh theo cng thc sau: Kh bt g c t ( ) (S%) ( s ) :

Ast : hp thu ca m u th thi im t = 5 pht, 30 pht. Act : hp thu ca m u i chiu thi im t = 5 pht, 30 pht.


7



2.1.3.2. Phng php m hnh beta-caroten - acid linoleic Nguyn tc: Da vo kh nng lm thay i mu ca h nh tng beta-caroten v acid linoleic ca cc cht th nghim. Cc cht c hot tnh chng oxy ha cng cao th kh nng bo v mu beta-caroten cng ln. o hp thu bc sng 470 nm. M t: Dng 1 ml beta-caroten (0,2 mg/ml) ha tan trong cloroform cho vo erlen c cha 0,02 ml acid linoleic v 0,2 ml tween 20. Bay hi ht cloroform di p sut gim. Cho vo hn hp 0,2 ml dung dch flavonoid th trong methanol nng 10-3M. Cho vo tip 50 ml nc ct ( bo ha vi oxygen trong vng 15 pht). Hn hp c lc u v 50 oC trong vng 120 pht. o hp thu UV ca m u th bc sng 470 nm ti thi im 0 pht, 60 pht v 120 pht. M u i chiu c tin hnh trong cng iu kin nhng khng s dng flavonoid. Hot tnh chng oxy ha c tnh theo cng thc sau: Ho t tnh ch ( ) (T%) ( s ) :

As0 : hp thu ca m u th thi im 0 pht. Ast : hp thu ca m u th thi im t = 60 pht, 120 pht Ac0 : hp thu ca m u i chiu thi im 0 pht Act : hp thu ca m u i chiu thi im t = 60 pht, 120 pht 2.2 .Tng quan v flavonoid v hot tnh chng oxy ho 2.2.1.Flavonoid 2.2.1.1.nh ngha: Flavonoid l mt nhm hp cht t nhin ln thng gp trong thc vt, phn ln c mu vng v c chia lm nhiu nhm khc nhau. Hu ht flavonoid c cu trc polyphenolic. 2.2.1.2.Ngun gc ca flavonoid Cng nh vitamin C, cc flavonoid c khm ph bi mt trong nhng nh sinh ho ni ting nht th k 20: Albert Szent Gyorgyi (1893 1986). ng nhn


8



gii Nobel nm 1937 vi nhng khm ph quan trng v c tnh ca vitamin C v flavonoid. 2.2.1.3.Cu trc v phn loi Flavonoid l mt nhm hp cht ln thng gp trong thc vt. Cho n nay c khong 4000 cht c phn lp v xc nh cu trc. Ch ring hai nhm hp cht flavon v flavonol mang nhm th l -OH v/hoc -OCH3 th theo l thuyt s cht tng hp c c th ln ti 38.627 cht. Cc flavonoid l nhng cht c cu to khung theo kiu diphenyl propan [C6C3-C6] hay ni cch khc chng c cu to khung c bn gm hai vng benzen A v B ni vi nhau qua mch 3 carbon (Hnh 1). Trong a s cc trng hp mch 3 carbon ng vng vi vng A v to nn d vng C c oxy (Hnh 2).B A

Hnh 1 . Khung c bn diphenyl propan (C6-C3-C6) S phn loi cc flavonoid da vo v tr ca gc aryl (vng B) v cc mc oxy ha ca mch 3C [3] gm cc nhm chnh nh sau: Eu-flavonoid l nhng cht c gc aryl v tr 2, gm c: flavon, flavonol, flavanon, antocyanidin, chalcon Isoflavonoid l nhng hp cht c gc aryl v tr 3, gm c: isoflavon, isoflavonol, isoflavanon. Neoflavonoid l nhng hp cht c gc aryl v tr 4, gm c: 4-arylchroman, 4-arylcoumarin, daldergion. Ngoi ra, ngi ta cn phn bit biflavonoid, triflavonoid cu to tng ng bi 2, 3 monomer flavonoid, v flavolignan l nhng flavonoid m phn t c mt phn cu trc lignan. Flavonoid c th tn ti dng aglycon (ch gm khung c bn), hoc dng glycosid (gm khung c bn gn vi cht ng cc v tr khc nhau).


9



O

O OH

O

OFlavon

OFlavonol

OFlavanon

O

O

OH

O

OIsoflavon

OIsoflavonol

OIsoflavanon

OH O OHAntocyanidin

OChalcon

ODihydrochalcon

Hnh 2 . Cu trc khung c bn ca cc flavonoid 2.2.1.5.ng dng ca flavonoid Hin ti trn th trng c rt nhiu sn phm t flavonoid nh cc thuc Daflon, Ginkor Fort, Legalon, cc loi thuc ny l cc phn on chit flavonoid t dc liu cho kt qu tt trong iu tr cc bnh l v mch mu, thn kinh, chng oxy ho, bo v t bo gan Cc thc phm chc nng nh Orthomo flavon F hay FFLAVIN 7, Lipo flavonoid plus, Flavonoid 1000mg (Davinci Laboratories) c dng h tr cho cc bnh nhn x va ng mch, tiu ng. Ngoi ra cn c cc sn phm dng chm sc da, tc cha flavonoid c chit t dc liu iu cho thy flavonoid l mt hp cht c tim nng, cn nghin cu su hn, nht l cc flavonoid tng hp nhm sng lc nhng hp cht thuc tinh khit, hot tnh mnh, hiu qu v am ton c nhng bc pht trin lm sng.


10



2.2.2.Hot tnh sinh hc ca flavonoid c nhiu nghin cu tng hp v kho st hot tnh sinh hc cc d n cht flavonoid v chalcon cho thy cc d n cht ny c tc dng sinh hc ng k trn c in vitro v in vivo. Cc tc dng sinh hc c chng minh bng thc nghim bao gm tc dng khng khun khng nm, tc dng khng vim, tc dng bo v tim mch, khng ung th Nhiu nghin cu gn y cho thy cc bnh nh ung th, x va ng mch, vim mn tnh c lin quan n s stress oxy ha (oxydative stress) do cc tc nhn oxy ha c hot tnh (reactive oxygen species) trong c th. Cc polyphenol m c bit l flavonoid c chng minh l nhng cht c kh nng chng oxy ha mnh do c kh nng trung ha cc gc t do bng cch ng vai tr l cht cho electron hay nguyn t hydro (hnh 3). H thng lin hp trong phn t flavonoid v mt vi nhm hydroxyl nh nhm OH v tr 3 trn d vng C v v tr 3,4 trn vng B c vai tr quan trng trong vic to thnh cc gc t do bn sau khi cho electron hay nguyn t hydro cho cc gc t do khng bn trong c th.

Hnh 3. S chuyn ha ca cc gc t do flavonoid sau khi cho mt nguyn t hydro


11



Ngoi kh nng thu dn hay trung ha cc gc t do, kh nng chng oxy ha ca flavonoid cn c bit n nh tnh cht c th to phc chelat vi ion kim loi nh ion Fe2+ c ch phn ng Fenton, lm gim tc phn ng oxy ha ca cc gc t do trong c th. C th c nhiu bng chng v kh nng chng oxy ha (kh nng thu dn cc gc t do) ca cc nhm ph flavonoid khc nhau nh flavon (luteolin, chrysin, apigenin), flavonol (quercetin, rutin, isoquercitrin), flavanon (taxifolin, hesperetin,), flavan-3-ol (catechin, epicatechin,), anthocyanidin( cyanidin chlorid, malvin,), chalcon (xanthohumol v cc d n cht ca xanthohumol), isoflavon (daidzein, genistein,) Cc cng trnh ch yu nghin cu v cc nhm hp cht quen thuc nh flavon, flavonol, flavanol v c nhiu trong rau qu con ngi n hng ngy, cn t nghin cu v kh nng chng oxy ha trn nhm chalcon. 2.3 Tng quan v QSAR 2.3.1.Gii thiu chung Kh nng to ra nhng cht hu c mi l khng l, d l trong ngnh dc hay nhng ng dng cho nng nghip, hng liu, nc hoa v thc phm. Vo nm 1994, chemical abstracts lit k hn 13 triu cht nhng ch mt phn rt nh chng c th c tng hp. Nu vic tm kim nhng sn phm mi ch bng cch tng hp v th nhng hp cht mi m khng c mt hng d n no th thc s l mt cng vic lu di v tn km. Vic nhng tnh cht ha hc khc nhau c tc dng sinh hc khc nhau c bit hng triu nm trc. Kh nng xc nh cu trc sm cho php ngi ta thnh lp nhng mi lien h cu trc tc dng (SAR Structure activity Relationship), l nhng quan st n gin m mt thay i xc nh trong cu trc ha hc c nh hng xc nh ln hot tnh sinh hc. Khi m cu trc ha hc (hay rng hn l tnh cht ha l hoc cc trng) c m t bng nhng thng s m t nh lng c th ta c th xy dng mi tng quan cu trc tc ng sinh hc mt cch nh lng (QSAR Quantitative Structure activity Relationship). S


12



nh lng y khng lin quan n vic tc dng sinh hc c nh lng c hay khng, mc d l mt nhm l n thng gp. Mc tiu ca nghin cu QSAR l tm ra m hnh c kh nng d on ng tin cy cho d n cht, nh nh hng thit k v tng hp nhng cht ph hp vi mc ch nghin cu trong v vn hp cht hu c cp trn. QSAR c in ch quan tm 2D QSAR (2 Dimensions QSAR) l nhng tnh ton ch da trn nhng thng s cng thc ho hc hai chiu. Mt cch tng qut, cn c: -3D QSAR (3 Dimensions QSAR): tnh ton da trn cc thng s m t cng thc ho hc trong khng gian 3 chiu. -HQSAR (Hologram QSAR): phn tch hnh nh phn t, thng s m t l cc phn nhnh cu trc. Mt cch phn chia khc QSAR bao gm: -Hi quy (Regression): kt qu thu c l tc dng sinh hc nh lng (nh IC50), bao gm hi quy tuyn tnh, hi quy phi tuyn. -Phn loi (Classification) hay BQSAR (Binary QSAR): cho kt lun c hay khng (chng hn c hot tnh khng st rt hay khng). 2.3.2.Phng php xy dng m hnh d on Bnh phng ti thiu tng phn (PLS Partial Least Squares) Nghin cu 2D QSAR hi quy tuyn tnh u tin p dng phng php hi quy a tuyn (MLR MultiLinear Regression). Phng php ny c nhc im l khng loi b c cc mi lin h c s tng quan ln gia cc thng s nn t c dng hoc khc phc bng cch kt hp vi k thut phn tch thnh phn c bn (PCA Principal Component Analysis), c tn gi l hi quy da trn thnh phn c bn (PCR - Principal Component Regression). Vi cch th hai ta s tin hnh tnh cc thnh phn c bn trc (PC - Principal Component) ri mi xy dng phng trnh hi quy bng MLR. Mt k thut khc l PLS cng dung nhng lng, ging nh PC, to ra t cc bin c lp, gi l cc bin n (LV Latent


13



Variable). Cc PC hay LV u l s kt hp tuyn tnh ca tp hp cc bin c lp. PC1 = a11v1 + a12v2 + a1 NvN PC2 = a21v1 + a22v2 + a2 NvN PCq = aq1v1 + aq2v2 + aq NvN LV1 = b11v1 + b12v2 + b1 NvN LV2 = b11v1 + b12v2 + b1 NvN LVq = bq1v1 + bq2v2 + bq NvN Nhng khc bit l PLS tnh LV v cc h s tng quan cng mt lc. y l quy trnh lp nhm kt hp bc PCA trong PCR vi bc hi quy. LV cng nh PC c tnh gii thch phng sai trong tp cc gi tr x trong khi v n gi s trc giao vi mt LV khc. V vy, LV u tin s gii thch phn ln phng sai trong tp c lp, LV th hai gii thch phn ln th hai v c tip nh vy. im khc nhau quan trng gia PLS v PCR l LV c to thnh m ti a ho s tng quan vi bin ph thuc. Khng nh phng trnh PCr ni m cc PC khng tham gia vo bt k mt th t ring no th LC s tham gia vo phng trnh PLS theo th t mt, hai, ba Mt im mnh cn cp ca PLS l c th tin hnh trn lng ln thng s m t. C th, vic xy dng tin hnh theo thut ton sau: Gi s, ta c m phn t, mi phn t c m t bi mt vector n hng (hay n phn t, n vector) gm cc s thc xi=(xi1xin), gm cc thng s m t cho phn t I (v d, hot tnh sinh hc, logP hay tnh khc x). Gi s mi phn t c mt trng s (con s th hin mc quan trng) km theo, Wi l mt s khng m. Nhng trng s ny c coi nh l xc sut tng i bt gp phn t km theo v thng l tt c u bng 1. Tuy nhin, trong vi ng dng, nhng trng s khng cn bng thng c dung. t W l tng cc trng s.


14



Mt m hnh tuyn tnh y c dng a0+aTx vi a0 l mt con s (scalar v hng) v a l mt vector n hng. Nhng thng s ny c la chn sao cho sai s bnh phng trung bnh (MSE mean square error) l nh nht ( ) [ ( )]

Bng cch ly vi phn MSE theo nhng thng s ny, ta thy chng phi tho mn nhng phng trnh sau, c gi l nhng phng trnh bnh thng (normal equations). ( )

(

)(

)

Phi cn thn khi gii cc phng trnh trn v S thng suy bin (singular) hoc gn suy bin. Nhng phng trnh bnh thng c gii bng cho ho ma trn. V sao S i xng v dng, tt c nhng gi tr ring ca n l mt s thc v khng m. V vy chng ta c th tnh mt ma trn trc giao Q v mt ma trn cho D sao cho v cc thnh phn ca ma trn D c xp theo th t gim dn. Ta ly p gi tr ring u tin sao cho tt c u dng v iu kin (gin tr ln nht ca p gi tr ring c chia cho gi tr nh nht ca p gi tr ring) nh hn ngng no c ci t trc. Ma trn cho o ngc gi D* sau c to thnh vi s nghch o p gi tr ring chn nm trn ng cho v bt c ch no bng 0. Cui cng, ta xc nh vector thng s a vi php ny gi l hi quy thnh phn c bn (PCR). Mt bin i ca PCR l bnh phng ti thiu tng phn (PLS) c dung xc nh cc thng s m hnh tuyn tnh. Phng php ny s to nhng c lng hi khc m c l th hn. Cng lp nhng phng trnh bnh thng nh trn, ta li tm mt c lng ca a khi S c th trong tnh trng xu. Mt cch t c l xy dng mt ma trn trng s VA = (v1,v2,,vA), vi vi l vector ct c . Phng


15



n hng, v A, mc ph hp ca PLS, s nguyn nh hn hay bng n. Trc tin ta c cc ct ca ma trn VA khi tnh cho ho Gram-Schmidt cc vector c to bng chui Krylov {b, Sb,S2b,, SA-1b}. Sau , c vector h s tng quan PLS Ath, ta gii phng trnh a =VA(VTASVA)-1 VTA. Mt thut ton xc nh c s ph hp ca PLS t c ti bc Ath khi . Tuy nhin, c th ta mun dung vector hi quy PLS bc thp hn ph hp vi m hnh tuyn tnh. Ch rng nu thut ton tip tc cho ti khi A=n, ma trn trng s s vung v c xp y (full rank). Vector hi quy kt qu l li gii ca nhng bnh phng ti thiu thng thng tng ng vi vic gii a=S1b.

Hnh 4: M phng m hnh gm 2 thng s, tm phng trnh tuyn tnh ca x m ti thiu ho phn d y


16



2.3.3.Phng php la chn thng s m t trong xy dng m hnh QSAR C hai l do m ta khng dng tt c thng s m t tnh ton c xy dng m hnh d on. l: ng ca d on. H s tng quan ph thuc vo c lch v phng sai. Cng nhiu thng s m t th lch cng nh nhng phng sai cng ln. V vy ci thin ng ca d on bng cch gim phng sai ca nhng gi tr d on, nn ngi ta gim thng s m t. Vic din gii ngha ca m hnh. Vi lng ln bin c lp, ta thng mun tm tp nh hn nhng nh hng mnh nht. la ch thng s m t xy dng m hnh tt nht (c kh nng d on tt nht) ta nh vo cng c phn tch ng u nhin (QSAR Contingency) trong phn mm MOE 2008.10 v phng php la chn phn hi (wrapper) vi chin thut tm kim ly thm (Forward Selection) trong phn mm WEKA 3.7.0. Phn tch ngu nhin y l mt ng dng thng k c thit k h tr la chn thng s m t cho QSAR. V c bn n phn tch tnh ng u nhin ng bin ca mi thng s m t vi gi tr hot tnh. N cho ra mt bng h s m ta c th da vo chn nhng thng s quan trng. t X l thng s m t phn t ng u nhin v Y l gi tr hot tnh ng u nhin. Ta mun tnh c mc cc bin ng u nhin Y v X lin quan vi nhau (hay ph thuc nhau), gi l m u ng u nhin gm m cp (yi,xi). P quan. Tnh ng bin ca hai bin X v Y ng u nhin c xc nh bi Cov(X,Y) = E(XY) - E(X) E(Y). H s tng quan tuyn tnh th hin tnh ng bin v mc hai bin tng quan tuyn tnh, c xc nh: [ ( ) ( ) ( )] ( ) ( )

Lun nm trong khong [0,1], bng 1 ngha l s tng quan tuyn tnh hon ton v bng 0 l hon ton khng c tng quan. Nu khc 0 th X v Y ph


17



thuc. Phn tch ng u nhin. L n lc xc nh mc hai bin ng u nhin ph thuc. Phn tch ny c biu din bi mt bng m mij l kt qu t vic tnh biu tn sut hai chiu trn cp s ca m u (yi,xi). Trong trng hp cc bin ng u nhin ri rc, i v j tri trn cc gi tr dng ca bin ng u nhin ri rc. Vi cc bin ng u nhin lin tc, i v j tri trn tp hp cc hp hoc khong trong cc m u c cho vo. Ta thy rng thng k: ( )

C phn phi chi thch hp. Hai h s kt hp thng c dng: h s ng u nhin C v cramers V c xc nh nh sau: ( ) ( )

Vi I v J l s hp i v j tng ng. C hai u nm trong khong [0,1], vi 1 ngha l ph thuc v 0 l khng ph thuc. Tuy nhin, trong thc t, khng c gi tr no t c 1. H s khng chc chn. Ta c th xc nh mt h s da trn entropy ca nhng phn phi Pr(X,Y), Pr(Y|X) and Pr(X|Y). H s khng chc chn entropy, U, c nh ngha:

Vi HXY, HX v HY theo th t l entropy ca cc phn phi Pr(X,Y), Pr(X) v Pr(Y). H s U lun nm trong khong [0,1], vi 1 l ph thuc hon ton v 0 l khng ph thuc. Cc thng s m t ph hp vi phng trnh QSAR khi: C > 0,6; V > 0,2; U > 0.2; R2 > 0,2.


18



Phng php la chn phn hi vi chin thut ly thm Vic dng bn h s nh trn ch gip ta gii hn c phn no s lng thng s so vi ban u. Nu ch chn nhng thng s c gi tr h s ln th cha hn cho m hnh tng quan tt. Do cn kt hp phng php chn lc khc l phn hi (wrapper) vi chin thut tm kim ly thm v cch nh gi t hp thng s bng thut ton hi quy a tuyn (MLR). C th, chin thut tm kim bt u vi h s chn k (intercept), l k thng s c ngha nht, sau mi bc ln lt thm vo m hnh mt thng s trong nhng thng s cn li. nh gi tng t hp thng s bng k thut nh gi cho dng thut ton hi quy tuyn tnh. Thng s cho s ci thin nhiu nht (m hnh nh nht c sai s d on mong i ti thiu) c gi li v tin hnh bc tip theo 2.3.4. Phng php nh gi cho k ln (k-fold cross validation) m hnh d on Nu tp d liu ln th s c chia lm ba phn: tp hun luyn, tp th nghim v tp ngoi. Vic nh gi m hnh c tin hnh trn tp th nghim v tp ngoi. Nhng thng th s lng cht khng nhiu nh mong mun nn c mt cch lm khc l ch chia d liu ban u lm hai phn: tp xy dng m hnh v tp ngoi. Thc cht, tp xy dng m hnh l gp chung tp hun luyn v tp th nghim trn. V va dng xy dng m hnh va nh gi kh nng d on ca m hnh. Cch nh gi lc ny l nh gi ni v mt phng php thng s dng l nh gi cho k ln, vi k l s ln chia nh tp xy dng m hnh. Thng thng chn k nh nht l 5 (s ln chia nh nht cho nh gi ng tin cy) v ln nht chnh l s cht trong tp xy dng m hnh, khi gi l nh gi cho LOO (leave one out). Ty s lng cht trong tp xy dng m hnh v cn bng gia lch phng sai m ta chn k thch hp. Cch tin hnh nh gi cho k ln nh sau: - Tp xy dng m hnh c chia lm k phn. - Ly (k 1) phn lm tp hun luyn xy dng m hnh th cp s dng thng


19



s m t chn trc . - nh gi m hnh th cp bng phn cn li c gi tr bnh phng h s tng quan gia gi tr d on v gi tr thc nghim R2 v cn bc hai ca tng bnh phng lch gi tr d on gi tr thc nghim RMSE. - Xo trn ng u nhin k ln tp xy dng m hnh v lp li t u. Kt qu, gi tr nh gi cho l trung bnh ca R2 (nu l LOO th l gi l Q2) v RMSE sau k ln lp. 2.3.5. Quy trnh thc hin nghin cu QSAR


20



Hnh 5: Cc bc phn tch trong 2D QSARChun b c s d liu Cu trc ho hc - Hot tnh sinh hc

Tnh ton thng s m t Thng s m t 2D (MOE, Dragon) Ti thiu ho nng lng (Sybyl)

Phn chia tp hp, xy dng v nh gi m hnh Tp xy dng m hnh (training set)-Tp nh gi ngoi(External set) Ng u nhin (Random), phn phi a dng (Diverse)

La chn thng s m t Tp hp xy dng m hnh (training set) Loi b cc thng s c tng quan cho Loi cc thng s c >15% gi tr 0 (excel)

Chia t l cc thng s m t Tp hp xy dng m hnh (training set) Chia t l trong khong 0-1(RapidMiner 5)

Chn lc thng s m t Tp hp xy dng m hnh (training set) Phn tch ng u nhin (QSAR-Contingency-MOE 2008.10 Phng php da trn s tng quan (CFS WEKA 3.7.0)

Xy dng m hnh QSAR Tp hp xy dng m hnh (training set) Bnh phng ti thiu tng phn (PLS MOE 2008.10) nh gi cho ni (LOO MOE 2008.10):XR2,XRMSE

Loi b cht gy nhiu (outlier) Tp hp xy dng m hnh (training set) Da vo Z score (Plot MOE 2008.10)

nh gi kh nng d on ngoi Tp hp nh gi ngoi (external set) R2,RMSE


ng dng m hnh trong d on Gii thch m hnh Xy dng th vin cc hp cht p dng m hnh d on tm ng vin

21



Chng 3: I TNG V PHNG PHP NGHIN CU


22



3. i tng v phng php nghin cu 3.1. i tng nghin cu Nghin cu ny xy dng phng trnh QSAR trn d liu IC50 ca 60 cht flavonoid bt k c tng hp trong cc bi bo khoa hc trong nc v quc t. Phng trnh c xy dng trn chng trnh ho tin hc l SYBYL, MOE 2008.10 cng cc chng trnh h tr khc. Phng trnh c xy dng phi t yu cu: R2 0.5 RMSE, XRMSE min XR2 0.4 3.2. Nghin cu QSAR 3.2.1. Thu thp c s d liu Qua nhiu bi bo khoa hc, sng lc c gn 150 hp cht c hot tnh thuc nhiu nhm cu trc khc nhau. Cu trc 2D ca cc cht c v bng phn mm ChemBioDraw Ultra 11.0, 3D ca cc cht c v bng phn mm ChemBio3D Ultra 11.0 Hot tnh chng oxy ho ca cc hp cht c nh gi bng cc gi tr IC50 c xc nh bng phng php o quang. Trong phng php o quang c hai cch o: S dng DPPH S dng -caroten, acid linoleic

Cu trc v gi tr hot tnh khng st ca cc cht c lu tr dng *.docx. Kt qu tng hp lu tr trong dng *.xlsx. T tp d liu phc tp trn cc hp cht c chn la theo tiu ch: (i) cng cch nh gi hot tnh chng oxy ho (IC50), (ii) cng n v o hot tnh (nM), (iii) cng phng php xc nh hot tnh, (iv) c gi tr cht i chiu tng ng. S lng cht khng qu t ( 50). Da vo cht i chiu c th quy i gi tr hot tnh ca cc cht theo quy tc tam sut nu chnh lch gia cc gi tr hot tnh ca cht i chiu trong cc


23



bi bo khc nhau t nm ln tr ln. Do cc IC50 c gi tr chnh lch nhau nhiu nn c i thnh pIC50 = -log (IC50) ph hp cho vic xy dng phng trnh tuyn tnh quan h cu trc tc dng.

3.2.2. Xy dng thng s m t Cu trc 2 chiu (2D 2 dimensions) v gi tr IC50 ca cc cht nghin cu c lu tr bng tp tin *.mdb trong phn mm MOE 2008.10 (Molecular Operating Environment phin bn 2008.10) tin hnh xy dng cc m hnh. Trc tin, cc cu trc 3D c ti thiu ho nng lng v ng lc hc phn t trong SYBYL. Sau , cc cu trc 2D c ti thiu ha nng lng nh cng c energy minimize loi b mt s sai st do xy dng cu trc th cng. Cc cu trc c kim tra li loi b vic xut hin nhng lin kt khng c thc sau khi ti thiu ha nng lng. iu ny l do cu trc c xy dng bng phn mm ChemBioDraw Ultra 11.0 2008, c th khng tng thch vi MOE. Sau , 184 thng s m t cu trc phn t 2D c tnh ton nh cng c descriptors trong MOE. Thng s m t th hin cu trc ha hc hay tnh cht vt l ca mt phn t bng cc gi tr s, c nh hng ti tc dng sinh hc. Phn mm MOE tnh c 327 thng s m t phn t gm ba nhm: - 2D: thng s m t 2D ch dng cc nguyn t v thng tin lin kt ca phn t tnh ton. Cu dng ring v ta 3D khng dng. - i3D: thng s m t 3D ni dng thng tin ta 3D v mi phn t, tuy nhin, chng khng quay v khng chuyn i cu dng. - x3D: thng s m t 3D ngoi cng dng thng tin ta 3D nhng cng i hi mt khung tham chiu tuyt i. Ty theo nh hng nghin cu m chn la tnh ton thng s m t ph hp. Nghin cu ny tin hnh xy dng m hnh th hin mi quan h nh lng cu trc tc dng trn cu trc 2 chiu ca cc hp cht c tnh khng st rt nn ch quan tm cc thng s 2D, bao gm 7 nhm.


24



Bng 1 :Cc nhm thng s m t phn t 2D tnh bng MOE STT 1 2 3 4 Nhm thng s m t 2D Tnh cht vt l Din tch b mt c phn chia nh m s nguyn t v s lin kt Ch s hnh dng Kappa v ch s lin kt Kier&Hall Thng s ma trn khong cch v ma trn lin k Thng s c trng cho cu trc 6 mang hot tnh (pharmacophore) Thng s in tch ring phn Tnh din tch b mt c in tch ring phn tng ng Th hin mi lin kt gia cc nguyn t vi nhau M t Khng ph thuc cu dng Tnh theo h s phn chia octanol/nc hay tnh khc x

5

7

3.2.3. Phn chia tp hp xy dng m hnh 2D-QSAR v nh gi m hnh xy dng, tp d liu ban u c chia lm 2 phn l tp xy dng m hnh (chim 80% d liu ban u) v tp ngoi. Tp d liu c phn chia ng u nhin (random) hoc phn chia diverse. 3.2.3.1 Phn chia ngu nhin Tp ngoi nh gi m hnh cn tnh khch quan nn phn chia tp hp ng u nhin: - nh s ng u nhin cho cc cht bng hm RAND trong MOE. - Sp theo th t tng dn v ly 20% u tin lm tp nh gi ngoi. 3.2.3.2. Phn chia diverse Mt cch phn chia khc l da trn cng c diverse subset trong MOE, sp xp cc cht trong tp d liu da trn khong cch t cht ny n cht khc.


25



Th t sp xp cho php ly ra mt tp con gm nhng cht xa nht so vi cht xp th nht, l cht u tin v tr u tin trong tp d liu ban u. Cht xa nht trong nhng cht cn li c chn sp th t tip theo. Cht xa nht l cht c gi tr nh nht ca cc khong cch ti nhng cht xp hng l ln nht. Lp li qu trnh ny cho ti khi s cht mong mun. Cc cht khng c nh s c cng s th t l s ln nht. V cht u tin (c s nh nht) c xp cao nht nn th t sp xp ph thuc vo th t ban u ca d liu. chun b d liu cho vic xp hng, nn xp th t cc cht trc, chng hn theo nng lng, nh th cht c nng lng thp nht xut hin u tin. C nhiu cch tnh khong cch gia hai cht ph thuc vo d liu s dng l thng s m t, du vn tay (fingerprint) hay d liu cu dng (conformation data). Vi thng s m t, khong cch gia hai cht l khong cch Euclide gia hai im i din cho hai cht trong khng gian n-chiu. Mc ch ca diverse l chn ra mt tp con khc bit nht trong tp hp ban u. Vic ny thch hp cho vic chn tp xy dng m hnh c tnh i din cho c tp d liu ban u. 3.2.3. La chn thng s m t Tp xy dng m hnh loi th v chia t l c chn thng s m t nh cng c QSAR Contingency trong phn mm MOE v cng c select attributes trong phn mm WEKA 3.7.0. Chn thng s m t trong WEKA gm 2 chc nng tm kim v nh gi tp hp thng s chn c theo tng bc tm kim. La chn chin lc tm kim hiu qu t tn ti nguyn my, khng b st m hnh tt v ph hp ln ca tp d liu v thut ton nh gi thng s. Trong nghin cu ny, chin thut tm kim ly thm c s dng, phng php nh gi thng s l phn hi vi thut ton hi qui a tuyn. 3.2.4. Thut ton QSAR S dng cng c QSAR Model trong phn mm MOE xy dng m hnh. La chn li thng s m t bng cch loi dn theo h s tng quan vi pIC50 v nh gi bng LOO. Dng gi tr Z-score loi cht gy nhiu. Xy


26



dng li m hnh vi nhng tp loi nhiu. 3.2.5. nh gi m hnh Mc tiu ca nghin cu QSAR l xy dng c m hnh c kh nng d on tt gi tr d on v gi tr thc gn nhau. iu th hin qua gi tr p, bnh phng h s tng quan R2 v cn ca tng bnh phng phn d RMSE ca tp xy dng m hnh. Cc gi tr ny c thm nh bng nh gi ni (nh gi cho LOO) v nh gi trn tp ngoi. nh gi cho LOO c tin hnh ng thi vi xy dng m hnh bng MOE. Cc thn s nh gi l gi tr trung bnh ca bnh phng h s tng quan ca cc m hnh tha cp Q2 v RMSE nh gi cho. Tp ngoi c tch ring u tin, khng tham gia vo quy trnh xy dng m hnh m bo tnh khch quan cho vic nh gi kh nng d on ca m hnh. ng dng tp ngoi vo m hnh xy dng bng cng c model evaluate ca MOE. Phn ln cc gi tr d on ca tp ngoi phi nm trong khong tin cy 95% d on ng ca m hnh. V cn c cc thng s nh gi l bnh phng h s tng quan R2 v cn ca tng bnh phng phn d RMSE gia gi tr d on v gi tr thc nghim ca cc cht trong tp ngoi.


27



Chng 4: KT QU V BN LUN


28



4.Kt qu v bn lun 4.1.C s d liu Qua qu trnh thu thp v chn lc, c s d liu gm 60 cht vi ch s IC50 (Ph lc 1). Da vo v hnh 2D v 3D ca cc cht v tnh ra pIC50=-lg IC50. Sau , tp d liu c nhp vo MOE vi dng *.mdb gm c cng thc ho hc 3D, tn cht v ch s pIC50. Trong chng trnh MOE, cc cht c tnh cc thng s m t phn t. Tp xy dng m hnh ca tng m hnh c s lng thng s m t chia t l c dng la chn thng s s dng cng c QSAR Contingency v/hoc chin thut tm kim trong phn mm WEKA nh trnh by trong phn PPNC. Lng thng s m t chn ra ti a bng 1/5 s lng cht trong tp hp. Cc thng s m t chn c cho mi m hnh c dng xy dng phng trnh hi quy bng phng php bnh phng ti thiu tng phn. Phng trnh hi qui th hin mi lin quan nh lng gia cu trc (thng s m t) v tc dng chng oxy ho , c dng: y=a0+aixi. Trong a0 l h s chn ca phng trnh, nu tt c cc thng s m t xi=0 th hot tnh y=a0; ai l h s hi qui ca tng thng s xi, th hin t l v chiu hng thay i hot tnh sinh hc khi gi tr thng s thay i. C th, nu ai dng th cu trc c thng s m t xi s cho hot tnh tng v ngc li. Phng trnh hi quy bao gm cc thng tin trn v h s tng quan cho ca tng cp thng s m t, tt c u nh hn 0.90 (90%). Cc thng s m t c h s tng quan cho cao hn 0.90 th c xem nh l ging nhau v vic c mt c hai trong phng trnh l d tha, khin bnh phng h s tng quan ca c phng trnh cao hn so vi thc t. Kh nng d on ca cc m hnh c th hin bng cn bc hai sai s chun (RMSE), bnh phng h s hi qui (R2), gi tr p ca tp xy dng. nh gi li kh nng d on s dng cc h s nh gi ni gm cn bc hai sai s (XRMSE), bnh phng h s hi qui (Q2) ca nh gi cho LOO v cc h


29



s nh gi ngoi khi ng dng tp ngoi c phn phi ng u nhin hoc diverse vo m hnh gm RMSE v R2. 4.2.M hnh QSAR da trn mt thng s m t phn t Sau khi chn lc cc thng s m t bng QSAR Contingency, da vo s so snh tng quan thng s m t vi pIC50, lip_don l thng s m t c tng quan cao nht l 85 (hnh 6), thc hin xy dng phng trnh trn thng s m t ny c phng trnh (I). V cc thng s c s tng quan vi nhau trn 80 th chng ta ch chn mt thng s m t c s tng quan tt nht vi pIC50. Cc thng s m ta la chn c lit k trong bng 2. Bng 2: Thng s m t Thng s m t b-1rotN Phng trnh R2 RMSE 0.65318 XRMSE XR2 0.67642 0.25599

pIC50 =-1.60003-0.22447 0.30192 * b_rotN

PEOE_VSA+1

pIC50 =-1.04112-0.01700 0.29304 * PEOE_VSA+1

0.65732

0.68786

0.23613

PEOE_VSA+2

pIC50 =-2.63808+0.02576 0.20824 * PEOE_VSA+2

0.69563

0.72413

0.14851

PC+

pIC50 =-3.48780+0.40983 0.26497 * PC+

0.67025

0.70021

0.20776

lip_don

pIC50 =-3.09200+0.40233 0.71945 * lip_don

0.41408

0.42415

0.70573

SMR_VSA3

pIC50 =-3.31805+0.03920 0.23071 * SMR_VSA3

0.68569

0.71249

0.17473

logP(o/w)

pIC50 =-0.59580-0.54516 0.28092 * logP(o/w)

0.66293

0.68673

0.23182


30



Hnh 6: tng quan gia cc thng s vi pIC50

Vy th phng trnh (I) l pIC50 =-3.09200+0.40233 * lip_don vi h s lip_don l tng s H v OH trong phn t. M hnh c xy dng gm 60 cht thuc nhiu nhm cu trc. RMSE th hin sai s gia pIC50 d on v thc nghim l 0.41408, tng ng IC50 l 2.5nM, sai s ny nh. Mc tng quan gia gi tr d on v thc nghim l 71.9%, tng i tt. Cc gi tr tng t khi thc hin nh gi cho. 4.3.M hnh QSAR tng qut T 184 thng s m t cu trc khng gian tnh ton t MOE, cc thng s m t phn t c la chn bng php hiu chnh ca Forward Selection, s dng thut ton MLR, nh gi tr s p ca mi thng s, kt qu nh gi cho LOO v cui cng a ra m hnh c 7 thng s. Cc thng s c trnh by bng. Sau khi xy dng phng trnh mt thng s m t, da trn cc thng s m t phn t, thc hin xy dng m hnh QSAR tng qut da trn by thng s m


31



t khng c s tng quan l n nhau (hnh 6). M hnh c phng trnh (II) RMSE = 0.35247, R2= 0.79672, XRMSE = 0.40881, XR2= 0.72942. pIC50 = -2.10317 -0.00339 * PEOE_VSA+2 +0.05470 * PC+ +0.17340 * lip_don +0.02805 * SMR_VSA3 -0.09223 * logP(o/w) -0.01707 * PEOE_VSA+1 +0.02086 * b_rotN


32



B ng 3: Cc thng s xy dng phng trnh ngha thng s Tng in tch dng b mt lin kt Van der Waals ti gi tr 0. 2 PEOE_VSA+2 Tng in tch dng b mt lin kt Van der Waals ti gi tr 2. 3 PC+ Tng cc in cc qi

STT 1

Tn thng s PEOE_VSA+1

4

lip_don

Tng s thnh phn OH v H

5 6

SMR_VSA3 logP(o/w)

tng s vi sao cho Ri trong khong (0.35,0.39]. Log ca h s phn vng octanol / nc (bao gm c hydrogens ngm). Thuc tnh ny c tnh ton t mt loi m hnh tuyn tnh nguyn t [LOGP 1998 vi r2 = 0,931, RMSE = 0,393 trn 1.827 phn t. S ca lin kt xoay hng c. Lin kt l xoay c nu n c th t 1, khng phi l trong vng mt, v c t nht l hai phn t lin k ln

7

b_rotN

M hnh c xy dng gm 60 cht thuc nhiu nhm cu trc. RMSE th hin sai s gia pIC50 d on v thc nghim l 0.35247, tng ng IC50 l 2.25nM, sai s ny nh. Mc tng quan gia gi tr d on v thc nghim l 79.6%, tng i tt. Cc gi tr tng t khi thc hin nh gi cho.


33



4.4. ng dng - D on gi tr IC50 ca nhng cht ch c gi tr hot tnh phn trm (ph lc 2) - D on gi tr IC50 ca nhng cht ch c gi tr hot tnh nhm cc cht c phng php IC50 khc nhau.(ph lc 2) 4.5.Th nghim nh gi li

4.6.Bn lun Nghin cu a ra 2 m hnh c xy dng trn 60 cht flavonid khc nhau. Kt qu c trnh by trn, phng trnh u c cc ch tho iu kin xy dng phng trnh. R2 : th hin tin cy ca phng trnh c xy dng trn tp hp xy dng. RMSE : th hin sai s ca IC50 d on v IC50 thc t ca tp hp xy dng. XR2 : th hin tin cy ca phng trnh c xy dng trong nh gi cho trn tp hp xy dng. XRMSE : th hin sai s ca IC50 d on v IC50 thc t ca nh gi cho trn tp hp xy dng. 4.6.1. Phng trnh mt thng s Trong m hnh mt thng s m t, phng trnh c chn l phng trnh: pIC50 =-3.09200+0.40233 * lip_don Phng trnh xy dng trn thng s lip_don, thng s ny th hin s khc nhau ca s OH v H trong cng thc ho hc ca cc cht flavonoid. Vy ch cn s thay i s nguyn t H v OH ca mt cng thc ho hc ta s c IC50 mi. Tuy nhin v phng trnh c tin cy 71.9%, sai s gia IC50 d on v IC50 thc t 41.4% l cha hon ho nn IC50 d on ca phng trnh cn hn ch i vi cc cht c cng thc ho hc gn nh tng t nhau. 4.6.2. Phng trnh by thng s


34



V nhng hn ch trn ca phng trnh mt thng s m t, ta xy dng phng trnh trn 7 thng s m t. pIC50 = -2.10317 -0.00339 * PEOE_VSA+2 +0.05470 * PC+ +0.17340 * lip_don +0.02805 * SMR_VSA3 -0.09223 * logP(o/w) -0.01707 * PEOE_VSA+1 +0.02086 * b_rotN ngha cc thng s m t c trnh by bng 3. Phng trnh c xy dng c tin cy l 79,6%, sai s gia IC50 d on v IC50 thc t l 35.2%. Vi cc ch s ny th IC50 c d on t phng trnh ny tt hn hn so vi phng trnh mt thng s trn, khi cc IC50 ca cc cng thc ho hc gn nh tng t nhau c d on c s khc bit. 4.6.3. Th nghim nh gi li


35



Chng 5: KT LUN V NGH


36



5. Kt lun v ngh 5.1.Kt lun Qua qu trnh thc hin, ti t c mc tiu ra v thu c nhng kt qu sau: - Tp hp cc cu trc ha hc ca d n cht flavonoid c hot tnh chng oxy ha t cc ti liu tham kho trong v ngoi nc - Nghin cu xy dng mi quan h gia cu trc ha hc cc d n cht flavonoid v hot tnh chng oxy ha bng cc phn mm ha tin hc thch hp ng thi p dng thnh cng trong phn tch xy dng m hnh QSAR trn thng s m t 2 chiu v d on c kh nng khng oxi ho ca mt s cht flavonoid. Phn tch c s tng quan ca s OH v H trong phn t i vi kh ngng khng oxi ho qua phng trnh mt thng s m t vi R2= 0.71945, RMSE = 0.41408, XRMSE = 0.42415, XR2 = 0.70573. T , xy dng m hnh QSAR tng qut vi by thng s m t, th hin s tng quan gia lin kt phn t Van der Waals, tng s OH v H, tng s cc in cc, h s phn vng octanol/nc, s lin kt xoay hng vi RMSE = 0.35247, R2= 0.79672, XRMSE = 0.40881, XR2= 0.72942. Phng trnh trn c kh nng d on IC50 chnh xc hn phng trnh mt thng s khi c nhng cht c s OH v H l tng t nhau th v n c th d on c IC50 l khc nhau. 5.2. ngh V thi gian thc hin ti tng i hn ch nn ngun d liu tng hp c l khng nhiu. Hng m rng ca ti l: Tng hp ngun d liu nhiu hn, t xy dng m hnh tng qut hn v kt hp QSAR 3D a ra cng thc ti u nht Nghin cu qu trnh tng hp cc cht c hot tnh khng oxi ho cao c ngh trong ti. T , thc hin o kh nng khng oxi ho ca cht ny.


37

Documents

LUẬN VĂN HOÀN CHỈNH