William L. Jorgensen

Sterling Professor of Chemistry
Director, Division of Physical Sciences & Engineering, 2009-12
Member of Yale faculty since 1990

E-mail: william.jorgensen@yale.edu
Web site: http://www.JorgensenResearch.com

A tautomerase inhibitor bound to macrophage migration inhibitory factor (MIF).A tautomerase inhibitor bound to macrophage migration inhibitory factor (MIF).

Research Organic, medicinal, and computational chemistry including simulations of organic and enzymatic reactions, computer-aided drug design, and synthesis and development of therapeutic agents targeting infectious, inflammatory, and hyperproliferative diseases.

Computer-Aided Drug Discovery. Our approach features focused synthetic organic chemistry driven by state-of-the-art molecular design. The computations center on modeling protein-inhibitor complexes including docking for virtual high-throughput screening, growing of combinatorial libraries inside binding sites with BOMB, and lead-optimization guided by Monte Carlo free-energy simulations. Synthesis and optimization of the most promising leads are performed in our laboratory, and biological testing and crystallography are pursued with collaborators. The approach has allowed efficient discovery of extraordinarily potent anti-HIV, anti-inflammatory, and anti-cancer agents. Current protein targets include HIV-1 reverse transcriptase, MIF, hDM2, hDMX, Tdp1, and FGFR1 kinase.

Transition state for an SN2 reaction in TIP4P water.Transition state for an SN2 reaction in TIP4P water.

Modeling of Organic and Enzymatic Reactions. The aims include elucidation of reaction mechanisms, medium effects on reaction rates, and effects of site-specific mutations on enzymatic reactions. A QM/MM approach is taken; the energetics of the reacting systems are described quantum mechanically with ab initio, DFT, or advanced semiempirical QM methods such as our PDDG/PM3 procedure. The environment including solvent molecules are represented using molecular mechanics and the sampling is normally performed with Monte Carlo statistical mechanics.  Our group is also recognized as a leader in the development of force fields for water, organic and biomolecular systems and in the development of comprehensive software for molecular modeling (BOSS and MCPRO).

A.B. Princeton University, 1970
Ph.D. Harvard University, 1975

A.C. Cope Scholar Award, 1990
Fellow, American Association for the Advancement of Science, 1994
ACS Award for Computers in Chemical and Pharmaceutical Research, 1998
Sato International Award, 2004
ISQBP Award in Computational Biology, 2004
American Academy of Arts and Sciences, 2007
Fellow, American Chemical Society, 2009
International Academy of Quantum Molecular Science, 2010
U.S. National Academy of Sciences, 2011
ACS Joel H. Hildebrand Award in the Theoretical and Experimental Chemistry of Liquids, 2012

Recent Publications
W.L. Jorgensen. Efficient Drug Lead Discovery and Optimization. Acc. Chem. Res. 2009, 42, 724-733.

O. Acevedo & W.L. Jorgensen. Advances in QM/MM Simulations for Organic and Enzymatic Reactions. Acc. Chem. Res. 2010, 43, 142-151.

M. Bollini, R.A. Domaoal, V.V. Thakur, R. Gallardo-Macias, K A. Spasov, K.S. Anderson & W.L. Jorgensen. Computationally-Guided Optimization of a Docking Hit to Yield Catechol Diethers as Potent Anti-HIV Agents. J. Med. Chem. 2011, 54, 8582-8591.

W.G. Lee, R. Gallardo-Macias, K.M. Frey, K.A. Spasov, M. Bollini, K.S. Anderson & W.L. Jorgensen. Picomolar Inhibitors of HIV Reverse Transcriptase Featuring Bicyclic Replacement of a Cyanovinylphenyl Group. J. Am. Chem. Soc. 2013, 135, 16705-16713.

D.J. Cole, J. Tirado-Rives & W.L. Jorgensen. Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering. J. Chem. Theory Comput. 2014, 10, 565-571.

William L. Jorgensen

Research Interests