The purpose of the research program is to develop and use computational methods to facilitate the discovery of new drugs for treatment of human diseases. The approach combines state-of-the-art technology for molecular design, synthetic organic chemistry, biological assaying, and crystallographic determination of structures of the designed molecules bound to their protein targets. The PI's research program spans fundamental advances in the development of software and methodology, detailed modeling of protein-ligand binding, inhibitor design, and synthesis. Collaborations with biologists provide the determinations of biological activity and macromolecular structures. The PI's group has developed computational tools to speed lead optimization for potency, while being mindful of the need for desirable pharmacological properties. Lead generation is facilitated with the ligand-growing program BOMB, and lead optimization is guided by free-energy perturbation (FEP) calculations using Monte Carlo (MC) statistical mechanics for the unbound ligands and protein-ligand complexes in water. Three specific biomolecular targets are addressed: HIV-1 reverse transcriptase (HIV-RT), macrophage migration inhibitory factor (MIF), and tyrosyl-DNA phosphodiesterase 1 (Tdp1). Successful development of inhibitors for these targets is intended to yield new chemotherapies for treatment of HIV/AIDS, inflammatory diseases, malaria, and cancer. The viability of the approach has been well established through the discovery of numerous potent inhibitors of several proteins. This includes discovery of agents that impede HIV replication and both antagonists and agonists of the signaling of the cytokine MIF. A series of the MIF antagonists has advanced to pre-clinical development as anti-inflammatory drugs for treatment of rheumatoid arthritis. Other MIF-signaling inhibitors that we have prepared are showing great potential for treatment of ischemic cardiac injury and ovarian cancer. Though much work remains to be done to find optimal inhibitors of HIV replication and regulators of MIF signaling, Tdp1 is a promising new target for cancer chemotherapy that is also under investigation.

Public Health Relevance

We develop and apply computational procedures and software for the efficient design of potential drugs. Coupled with synthetic organic chemistry and biological assaying we are discovering molecules with the intention of using them to combat HIV/AIDS, inflammatory diseases, heart disease, malaria, and cancer.

National Institute of Health (NIH)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
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Preusch, Peter
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Yale University
Schools of Arts and Sciences
New Haven
United States
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Cole, Daniel J; Tirado-Rives, Julian; Jorgensen, William L (2015) Molecular dynamics and Monte Carlo simulations for protein-ligand binding and inhibitor design. Biochim Biophys Acta 1850:966-71
Parker, Christopher G; Dahlgren, Markus K; Tao, Ran N et al. (2014) Illuminating HIV gp120-Ligand Recognition through Computationally-Driven Optimization of Antibody-Recruiting Molecules. Chem Sci 5:2311-2317
Sharma, Hitesh; Landau, Mark J; Sullivan, Todd J et al. (2014) Virtual screening reveals allosteric inhibitors of the Toxoplasma gondii thymidylate synthase-dihydrofolate reductase. Bioorg Med Chem Lett 24:1232-5
Acevedo, Orlando; Jorgensen, Wiliiam L (2014) Quantum and Molecular Mechanical (QM/MM) Monte Carlo Techniques for Modeling Condensed-Phase Reactions. Wiley Interdiscip Rev Comput Mol Sci 4:422-435
Marchand, Christophe; Huang, Shar-yin N; Dexheimer, Thomas S et al. (2014) Biochemical assays for the discovery of TDP1 inhibitors. Mol Cancer Ther 13:2116-26
Frey, Kathleen M; Gray, William T; Spasov, Krasimir A et al. (2014) Structure-based evaluation of C5 derivatives in the catechol diether series targeting HIV-1 reverse transcriptase. Chem Biol Drug Des 83:541-9
Kumar, Vidya P; Cisneros, Jose A; Frey, Kathleen M et al. (2014) Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis thymidylate synthase-dihydrofolate reductase. Bioorg Med Chem Lett 24:4158-61
Pantouris, Georgios; Rajasekaran, Deepa; Garcia, Alvaro Baeza et al. (2014) Crystallographic and receptor binding characterization of Plasmodium falciparum macrophage migration inhibitory factor complexed to two potent inhibitors. J Med Chem 57:8652-6
Mislak, Andrea C; Frey, Kathleen M; Bollini, Mariela et al. (2014) A mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptase. Biochim Biophys Acta 1840:2203-11
Bollini, Mariela; Frey, Kathleen M; Cisneros, Jose A et al. (2013) Extension into the entrance channel of HIV-1 reverse transcriptase--crystallography and enhanced solubility. Bioorg Med Chem Lett 23:5209-12

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