Dr. Michael K. Gilson, Computer-Aided Drug Design, Biophysical Theory and Modeling

Research Summary: Modeling and informatics of molecular recognition

Our long-term interest is to speed the design of biomedically useful targeted molecules, including drugs and functional host-guest systems, by developing a better understanding of the physical determinants of binding affinity. We also develop computational methods for modeling and studying binding, and we are interested in collaborations focusing on practical applications, validation of methods, improving algorithms, and elucidating theory.

We developed the “mining minima” approach to computing affinities, which has given encouraging agreement with experiment for host-guest and protein-ligand systems, and we continue to develop and apply this approach. We also seek to deepen our understanding of entropy’s role in molecular recognition, and have developed new methods to address this intriguing and challenging problem. Advances in this area promise to yield new insights to help guide the design of high-affinity ligands.

We are exploring the application of ideas of mechanical stress at the molecular level. This promises to provide explanatory mechanism for functional behaviors such as allostery.

We continue to improve and expand a widely used, web-accessible database of measured protein-ligand binding affinities, BindingDB (www.bindingb.org).

Academic Achievements

Education: A.B. Bioengineering Magna cum Laude, (1981) Harvard College; Ph.D. in Biochemistry and Molecular Biophysics (1988) Columbia University; M.D. (1989) Columbia University College of Physicians and Surgeons.

Awards and Honors: Detur Prize (1978); John Harvard Scholarship (1978,1979); Tau Beta Pi Engineering Award (1981); Alfred Steiner Award (1987); Associated Medical Schools Award (1987); Louis Gibofsky Memorial Prize (1989); Howard Hughes Medical Institute Physician Research Fellowship (1991-94).

Leadership Experience: Chair, NIH MSFD study section (2007-2008); Founder and CSO, VeraChem LLC. (2000-present); Vice-Chair, Faculty Senate, University of Maryland Biotechnology Institute (2008- 2009); Organizer, Keystone Symposium on Computer-Aided Drug Design (2010); Editorial Advisory Boards: J. Med. Chem., Biopolymers, etc.

Key Contributions to Pharmaceutical Sciences

• Developed statistical thermodynamic framework underlying calculation of binding free energies.
• Elucidated role of configurational entropy in molecular recognition.
• Contributed to structure-based development of mutation-resistant HIV-protease inhibitors

• Developed BindingDB, a public, web-accessible database of measure protein-small molecule binding affinities.

• Developed mining minima approach to computing host-guest and protein-small molecule affinities.

Selected Recent Publications (from 100 peer reviewed articles)

Gilson et al. (2007) Calculation of protein-ligand affinities. Annu Rev Biophys Biomol Struct 36:21-42.

Rekharsky et al. (2007). A synthetic host-guest system achieves avidin-biotin affinity by overcoming enthalpy–entropy compensation. Proc. Nat. Acad. Sci. USA, 104:20737-20742.

Altman et al. (2008). HIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants. J.Am.Chem.Soc., 130:6099-6113.

Killian et al. (2009). Configurational entropy in protein-peptide binding. Computational study of Tsg101 UEV domain with an HIV-derived PTAP nonapeptide. J. Molec. Biol., 389:315-335.

Moghaddam et al (2009). Host-guest complexes with protein-ligand-like affinities: Computational analysis and design. J. Am. Chem. Soc. 131:4012-4021.

Gilson et al. (2010) Stress analysis at the molecular level: A forced cucurbituril-guest dissociation pathway. J. Chem. Theo. Comput. 6:637-646.

Potential Collaborative Programs with the Pharmaceutical Industry

• Novel algorithms for affinity prediction, including contributions of configurational entropy.
• Broad perspective of computational design in chemical and clinical context.