Department of Chemistry
Yale University
225 Prospect Street
PO Box 208107
New Haven CT 06520 8107
203 432 3915

William L. Jorgensen

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

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

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 and hyperproliferative diseases.

Computer-Aided Drug Design. 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 agents and is also being applied to seek drugs to combat cancer, inflammatory, and neurological diseases.

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 software for molecular modeling in general.

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

Honors
A. C. Cope Scholar Award, 1990
ACS Award for Computers in Chemical and Pharmaceutical Research, 1998
ISQBP Award in Computational Biology, 2004
Sato International Award, 2004
American Academy of Arts and Sciences, 2007

Recent Publications
W. L. Jorgensen. The Many Roles of Computation in Drug Discovery. Science 2004, 303, 1813-1818.

W.L. Jorgensen & J. Tirado-Rives. Potential Energy Functions for Atomic-Level Simulations of Water and Organic and Biomolecular Systems. Proc. Nat. Acad. Sci. USA 2005, 102, 6665-6670.

J.T. Kim, A.D. Hamilton, C.M. Bailey, R.A. Domaoal, L. Wang, K.S. Anderson, & W.L. Jorgensen. FEP-Guided Selection of Bicyclic Heterocycles in Lead Optimization for Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase. J. Am. Chem. Soc. 2006, 128, 15372-15373.

I. Tubert-Brohman, O. Acevedo, & W.L. Jorgensen. Elucidation of Hydrolysis Mechanisms for Fatty Acid Amide Hydrolase and its Lys142Ala Variant. J. Am. Chem. Soc. 2006, 128, 16904-16913.

G. Barreiro, J.T. Kim, C.R. Guimaraes, C.M. Bailey, R.A. Domaoal, L. Wang, K.S. Anderson, & W.L. Jorgensen. From Docking False-Positive to Active Anti-HIV Agent. J. Med. Chem. 2007, 50, 5324-5329.