Computational Science and Drug Discovery

McCammon Group, UCSD/HHMI

Molecular Dynamics Simulation

McCammon, Gelin & Karplus, Nature (1977)

Molecular Mechanics

nVkbbkV n cosTorsions

2o

Angles

2o

BondsBond

Pairs Nonbonded

2

Pairs Nonbonded

612 r

eZZC

r

B

r

A ji

Bond & Bond Angle Potential

e.g., propane

Torsional (Dihedral) Potential

e.g., butane

kJ/mol 6 with ,3 33torsion VVV cos

Molecular Mechanics

nVkbbkV n cosTorsions

2o

Angles

2o

BondsBond

Pairs Nonbonded

2

Pairs Nonbonded

612 r

eZZC

r

B

r

A ji

van der Waals Interactions – short ranged

often represented by the Lennard-Jones formula:

612LJ r

B

r

AV

E.g. – Liquid Argon

Pairs Nonbonded

612 r

B

r

AV

No bonds, angles, ortorsions, so just have

Electrostatics – long ranged

nm) 0.25(contact in Cl and Nafor kJ/mol560 -e rV

Forces

NV r,,r,r 21

iii

i z

V

y

V

x

VV kjiiF

Energy Minimization: Steepest Descent

(recall, )

Molecular Dynamics Simulation

2

2

d

d

tmm iii

ii

raF

2

2

2

d

d

2

1

d

dt

t

xt

t

xtxttx

2)(2

1)( ttattvtxttx

Molecular Dynamics Simulation

McCammon, Gelin & Karplus, Nature (1977)

HIV/AIDS

1981: AIDS first described

1983: retrovirus HIV-1 identified

HIV-1 Enzymes:

Reverse Transcriptase (RNA to DNA)

Integrase (DNA into human genome)

Protease (Makes pieces of new HIV)

Target Flexibility

HIV-1 Protease

AIDS Deaths in the US

0

10000

20000

30000

40000

50000

60000

Relaxed Complex Method

Protein “snapshots” from simulation Rapid docking of ligand to snapshots Rescoring for higher accuracy Two-site binders with flexible linkers

Lin, Perryman, Schames & McCammon, J. Amer. Chem. Soc. (2002)

Initial Tests with FKBP-12

Standard MD in water, 2 ns

Fluctuation of Binding Site

AutoDocking of Ligand

More Accurate Rescoring

ABo

BA

AB

AB

BA2

ooAB 8

ln VPZZ

ZCRTG

AN,0

AN,A

AA rrr deZ

ZZ WU

Gilson, Given, Bush & McCammon, Biophys. J. (1997)

Bridging Water Molecules

Hamelberg & McCammon, J. Amer. Chem. Soc. (2004)

Copyright ©1999 by the National Academy of Sciences

Goldgur, …& Davies, Proc. Natl. Acad. Sci. USA (1999)

HIV Integrase and 5CITEP

Copyright ©1999 by the National Academy of Sciences

Goldgur, …& Davies, Proc. Natl. Acad. Sci. USA (1999)

5CITEP Contacts Between Asymmetric Units

Initial Relaxed Complex Results

Schames, … & McCammon, J. Med. Chem. (2004)

Butterfly Compounds

Schames, … & McCammon, J. Med. Chem. (2004)

Docked Butterfly Compounds

Schames, … & McCammon, J. Med. Chem. (2004)

Merck & Co. Strategy

New Class of HIV Drugs: Merck & Co.

“ Exploration of the structural basis for this unexpected result provides insights into this class of antiviral agents and suggests an approach to the development

of integrase inhibitors with unique resistance profiles.” D. Hazuda et al., Proc. Natl. Acad. Sci. USA (Aug. 2004).

Refers to Schames, et al. (2004).

Discovery of unexpected binding site in HIV-1 Integrase using MD and AutoDock: Schames, … & McCammon, J. Med. Chem. (released on web, March 2004)

L-870812  MK-0518

May, 2006 – Phase III Clinical Trials http://clinicaltrials.gov/show/NCT00293254

Metalloenzyme Inhibitors

Puerta, Mongan, Tran, McCammon, & Cohen. J. Amer. Chem. Soc. 127, 14148-14149 (2005).

(e.g., Trypanosoma brucei, T. cruzi)

Supramolecular Targets – The Ribosome

Trylska, J., V. Tozzini, J.A. McCammon. Biophys. J. 89, 1455-1463 (2005).

(e.g., antibiotics)

Structural Design

Acknowledgments

grad. students postdocs senior collabs.*Nathan Baker *Steve Bond *C. Bajaj Jennifer Bui Chia-en Chang Mike Holst Yuhui Cheng Xiaolin Cheng *Robert Konecny David Minh Joachim Dzubiella *Jeremy Kua John Mongan Barry Grant *Jung-Hsin Lin *Alex Perryman Justin Gullingsrud Steve Sine Julie Schames *Donald Hamelberg Susan Taylor*Tongye Shen *Richard Henchman *Valentina Tozzini Jason Smart Richard Law *Joanna Trylska Jessica Swanson Ben-Zhuo Lu *Chung Wong*Kaihsu Tai *Sanjib Senapati *Yingkai Zhang Sylvia Tara *Dave Sept David Zhang

van der Waals – short ranged

kJ/mol1LJ V for atoms in contact nm3.0r

Molecular Mechanics

nVkbbkV n cosTorsions

2o

Angles

2o

BondsBond

Pairs Nonbonded

2

Pairs Nonbonded

612 r

eZZC

r

B

r

A ji

Electrostatic Interactions

represented by Coulomb’s law: r

eZZCV

221

e

mol

kJ140 21

e r

ZZV if r is in nm

E.g. – Liquid Water

Bonds and angles areusually constrained, so

Pairs Nonbonded

2

Pairs Nonbonded

612 r

eZZC

r

B

r

AV ji

Explicit Solvation

Pairs Nonbonded

2

Pairs Nonbonded

612 r

eZZC

r

B

r

AV ji

Implicit Solvation

Pairs Nonbonded

2

Pairs Nonbonded

612 r

eZZC

r

B

r

AV ji

Ala-Asp-Lys in explicit water

nVkrrkV n cosTorsions

2o

Angles

2o

BondsBond

Pairs Nonbonded

2

Pairs Nonbonded

612 r

eZZC

r

B

r

A ji

Ala-Asp-Lys in implicit water

nVkrrkV n cosTorsions

2o

Angles

2o

BondsBond

Pairs Nonbonded

2

Pairs Nonbonded

612 r

eZZC

r

B

r

A ji

“Rugged” Energy Landscape

4-hydroxy-2-butanone and FKBP-12

Swanson, Henchman & McCammon, Biophys. J. 86, 67-74 (2004).

External Contributions

kJ/mol 17otrans G

kJ/mol 6orot G

Swanson, Henchman & McCammon, Biophys. J. 86, 67-74 (2004).

Cf. upper bound of about 80 kJ/mol (Jencks)

Approximations

Swanson, Henchman & McCammon, Biophys. J. 86, 67-74 (2004).

2 ln

8

trans rotB B AB

ABA B

C z z ZG RT

Z Z

2 ln

8

trans rotB B

AB AB A BC z z

G RT E E E

)()( xuxε )(1

oi

ii xxeδZ

)()()( 2 xuxκx

Poisson-Boltzmann equation (linearized)

IRTo

2 2

Linearized Poisson-Boltzmann equation also useful:

i

iic xxδz

kT

πexuxκxuxε )(

4)()()()(

22

)()( xuxε )(sinh)(2 xuxκ )(π4 2

ii

ic xxδz

kT

e )(sinh)(2 xuxκ )(

π4 2

ii

ic xxδz

kT

e

Poisson-Boltzmann equation: strong form

xxxgxu )()(

)()( xuxε

Merck & Co.

“Although both the biochemical and antiviral activities ofL-870,810 are analogous to the diketo acids, we provide evidence that these inhibitors exhibit discordant sensitivity to resistance mutations. Exploration of the structural basis for this unexpected result provides insights into this class of antiviral agents and suggests an approach to the development of integrase inhibitors with unique resistance profiles.”

D. Hazuda et al., Proc. Natl. Acad. Sci. USA 101, 11233 (2004).

Accelerated MD

EVVV

EVVV

(r)(r),(r)

(r)(r),(r)

(r))(

(r)(r)

2

VE

VEV

Hamelberg, Mongan & McCammon, J. Chem. Phys 120, 11919-11929 (2004)

Accelerated MD: Effect of V

(x)

V(x

)

x

α =1α= 50α= 100

Activation of Protein Kinase A

Gullingsrud, J., C. Kim, S.S. Taylor, J.A. McCammon.Dynamic binding of PKA regulatory subunit RI. Structure, 14, 141-149 (2006).