Research Projects

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

Inhibitors bound to HIV reverse transcriptase and macrophage migration inhibitory factor 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. (Image: Inhibitors bound to HIV reverse transcriptase and macrophage migration inhibitory factor.)

Modeling of Organic and Enzymatic Reactions

Transition states for an SN2 reaction in water and for a Diels-Alder reaction on a water surface. 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, namely BOSS and MCPRO. (Image: Transition states for an SN2 reaction in water and for a Diels-Alder reaction on a water surface.)

Recent Review Articles

The Many Roles of Computation in Drug Discovery. Jorgensen, W. L. Science 2004, 125, 1813-1818. doi:10.1126/science.1096361

Potential energy functions for atomic-level simulations of water, and organic and biomolecular systems. Jorgensen, W. L.; Tirado-Rives, J. Proc. Nat. Acad. Sci. USA 2005, 102, 6665-6670. doi:10.1073/pnas.0408037102

Perspective on Free-Energy Perturbation Calculations for Chemical Equilibria. Jorgensen, W. L.; Thomas, L. L. J. Chem. Theory Comput. 2008, 4, 869-876. doi:10.1021/ct800011m

Efficient Drug Lead Discovery and Optimization. Jorgensen, W. L. Acc. Chem. Res. 2009, 42, 724-733. doi:10.1021/ar800236t

Advances in QM/MM Simulations for Organic and Enzymatic Reactions. Acevedo, O.; Jorgensen, W. L. Acc. Chem. Res. 2010, 43, 142-151. doi:10.1021/ar900171c

Research Funding

Gratitude is expressed for support from:

  • Alliance for Lupus Research
  • Defense Advanced Research Projects Agency
  • National Foundation for Cancer Research
  • NIH, Institute for General Medical Sciences
  • NIH, Institute for Allergy and Infectious Diseases
  • National Science Foundation