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

X-ray crystal structureX-ray crystal structure of 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 wtih BOMB, and lead-optimization guided by Monte Carlo free-energy simulations. Synthesis and optimization of the most promising leads are performed in our laboratory; biological testing and crystallography are pursued either in our laboratory or with collaborators. The approach has allowed efficient discovery of extraordinarily potent anit-HIV, anti-inflammatory, and anti-cancer agents. Current protein targets include HIV-1 reverse transcriptase, CXCR4, MIF, parasitic TS-DHFRs, and JAK2 kinase.

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

Modeling Organic Chemistry and Biochemistry in Solution. The group has pioneered computational studies of chemistry in solution, helping enable the widespread activities today in modeling organic and biomolecular systems. This includes development and application of the OPLS force fields and TIPnP water models, free-energy methods for organic reactions and host-guest binding, improved semiempirical MO methods, protein dynamics in water, and mixed quantum and molecular mechanics (QM/MM) simulations for organic and enzymatic reactions. Emphasis has been placed on elucidation of reaction mechanisms, transition states in solution, and the origin of medium effects on reaction rates. Multiple activites continue in developing improved methodology and force fields.

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
Tetrahedron Prize, 2015

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.

W.G. Lee, K.M. Frey, R. Gallardo-Macias, K.A. Spasov, M. Bollini, K.S. Anderson, & W.L. Jorgensen. Picomolar Inhibitors of HIV-1 Reverse Transcriptase: Design and Crystallography of Naphthyl Phenyl Ethers. ACS Med. Chem. Lett. 2014, 5, 1259-1262.

W.L. Jorgensen. Scientific History and Recollections. J. Phys. Chem. B. 2015, 119, 624-632.

P. Dziedzic, J.A. Cisneros, M.J. Robertson, A.A. Hare, N.E. Danford, R.H.G. Baxter, & W.L. Jorgensen. Design, Synthesis, and Protein Crystallography of Biaryltriazoles as Potent Tautomerase Inhibitors of Macrophage Migration Inhibitory Factor. J. Am. Chem. Soc. 2015, 137, 2996-3003.

William L. Jorgensen

Research Interests