Computational Science and Drug Discovery McCammon Group, UCSD/HHMI

Molecular Dynamics Simulation McCammon, Gelin & Karplus, Nature (1977)

Molecular Mechanics

Bond & Bond Angle Potential e.g., propane

Torsional (Dihedral) Potential e.g., butane

Molecular Mechanics

van der Waals Interactions – short ranged often represented by the Lennard- Jones formula:

E.g. – Liquid Argon No bonds, angles, or torsions, so just have

Electrostatics – long ranged

Forces

Energy Minimization: Steepest Descent (recall, )

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

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 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 MK-0518 May, 2006 – Phase III Clinical Trials

Metalloenzyme Inhibitors Puerta, Mongan, Tran, McCammon, & Cohen. J. Amer. Chem. Soc. 127, (2005). (e.g., Trypanosoma brucei, T. cruzi)

Supramolecular Targets – The Ribosome Trylska, J., V. Tozzini, J.A. McCammon. Biophys. J. 89, (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 for atoms in contact

Molecular Mechanics

Electrostatic Interactions represented by Coulomb’s law: if r is in nm

E.g. – Liquid Water Bonds and angles are usually constrained, so

Explicit Solvation

Implicit Solvation

Ala-Asp-Lys in explicit water

Ala-Asp-Lys in implicit water

“Rugged” Energy Landscape

4-hydroxy-2-butanone and FKBP-12 Swanson, Henchman & McCammon, Biophys. J. 86, (2004).

External Contributions Swanson, Henchman & McCammon, Biophys. J. 86, (2004). Cf. upper bound of about 80 kJ/mol (Jencks)

Approximations Swanson, Henchman & McCammon, Biophys. J. 86, (2004).

Poisson-Boltzmann equation (linearized)

Linearized Poisson-Boltzmann equation also useful: Poisson-Boltzmann equation: strong form

Merck & Co. “Although both the biochemical and antiviral activities of L-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, (2004).

Accelerated MD Hamelberg, Mongan & McCammon, J. Chem. Phys 120, (2004)

Accelerated MD: Effect of 

Activation of Protein Kinase A Gullingsrud, J., C. Kim, S.S. Taylor, J.A. McCammon. Dynamic binding of PKA regulatory subunit RI . Structure, 14, (2006).