Computational Science and Drug Discovery Mc Cammon Group

Computational Science and Drug Discovery Mc. Cammon Group, UCSD/HHMI

Molecular Dynamics Simulation Mc. Cammon, 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

Molecular Dynamics Simulation Mc. Cammon, 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 Ø Protein “snapshots” from simulation Ø Rapid docking of ligand to snapshots Ø Rescoring for higher accuracy Ø Two-site binders with flexible linkers Lin, Perryman, Schames & Mc. Cammon, J. Amer. Chem. Soc. (2002)

Initial Tests with FKBP-12 Standard MD in water, 2 ns

Fluctuation of Binding Site

Auto. Docking of Ligand

More Accurate Rescoring Gilson, Given, Bush & Mc. Cammon, Biophys. J. (1997)

Bridging Water Molecules Hamelberg & Mc. Cammon, J. Amer. Chem. Soc. (2004)

HIV Integrase and 5 CITEP Goldgur, …& Davies, Proc. Natl. Acad. Sci. USA (1999) Copyright © 1999 by the National Academy of Sciences

5 CITEP Contacts Between Asymmetric Units Goldgur, …& Davies, Proc. Natl. Acad. Sci. USA (1999) Copyright © 1999 by the National Academy of Sciences

Initial Relaxed Complex Results Schames, … & Mc. Cammon, J. Med. Chem. (2004)

Butterfly Compounds Schames, … & Mc. Cammon, J. Med. Chem. (2004)

Docked Butterfly Compounds Schames, … & Mc. Cammon, J. Med. Chem. (2004)

Merck & Co. Strategy

New Class of HIV Drugs: Merck & Co. Discovery of unexpected binding site in HIV-1 Integrase using MD and Auto. Dock: Schames, … & Mc. Cammon, J. Med. Chem. (released on web, March 2004) “ 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). L-870812 MK-0518 May, 2006 – Phase III Clinical Trials http: //clinicaltrials. gov/show/NCT 00293254

Metalloenzyme Inhibitors (e. g. , Trypanosoma brucei, T. cruzi) Puerta, Mongan, Tran, Mc. Cammon, & Cohen. J. Amer. Chem. Soc. 127, 14148 -14149 (2005).

Supramolecular Targets – The Ribosome (e. g. , antibiotics) Trylska, J. , V. Tozzini, J. A. Mc. Cammon. Biophys. J. 89, 1455 -1463 (2005).

Structural Design

Acknowledgments grad. students *Nathan Baker Jennifer Bui Yuhui Cheng David Minh John Mongan *Alex Perryman Julie Schames *Tongye Shen Jason Smart Jessica Swanson *Kaihsu Tai Sylvia Tara postdocs *Steve Bond Chia-en Chang Xiaolin Cheng Joachim Dzubiella Barry Grant Justin Gullingsrud *Donald Hamelberg *Richard Henchman Richard Law Ben-Zhuo Lu *Sanjib Senapati *Dave Sept David Zhang senior collabs. *C. Bajaj Mike Holst *Robert Konecny *Jeremy Kua *Jung-Hsin Lin Steve Sine Susan Taylor *Valentina Tozzini *Joanna Trylska *Chung Wong *Yingkai 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 & Mc. Cammon, Biophys. J. 86, 67 -74 (2004).

External Contributions Cf. upper bound of about 80 k. J/mol (Jencks) Swanson, Henchman & Mc. Cammon, Biophys. J. 86, 67 -74 (2004).

Approximations Swanson, Henchman & Mc. Cammon, Biophys. J. 86, 67 -74 (2004).

Poisson-Boltzmann equation (linearized)

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

Merck & Co. D. Hazuda et al. , Proc. Natl. Acad. Sci. USA 101, 11233 (2004). “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. ”

Accelerated MD Hamelberg, Mongan & Mc. Cammon, J. Chem. Phys 120, 11919 -11929 (2004)

Accelerated MD: Effect of a

Activation of Protein Kinase A Gullingsrud, J. , C. Kim, S. S. Taylor, J. A. Mc. Cammon. Dynamic binding of PKA regulatory subunit RIa. Structure, 141 -149 (2006).