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)
National Institute of General Medical Sciences (NIGMS)
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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Lee, Won-Gil; Chan, Albert H; Spasov, Krasimir A et al. (2016) Design, Conformation, and Crystallography of 2-Naphthyl Phenyl Ethers as Potent Anti-HIV Agents. ACS Med Chem Lett 7:1156-1160
Cisneros, José A; Robertson, Michael J; Valhondo, Margarita et al. (2016) A Fluorescence Polarization Assay for Binding to Macrophage Migration Inhibitory Factor and Crystal Structures for Complexes of Two Potent Inhibitors. J Am Chem Soc 138:8630-8
Jorgensen, William L (2016) Computer-aided discovery of anti-HIV agents. Bioorg Med Chem 24:4768-4778
Cole, Daniel J; Vilseck, Jonah Z; Tirado-Rives, Julian et al. (2016) Biomolecular Force Field Parameterization via Atoms-in-Molecule Electron Density Partitioning. J Chem Theory Comput 12:2312-23
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
Vilseck, Jonah Z; Tirado-Rives, Julian; Jorgensen, William L (2015) Determination of partial molar volumes from free energy perturbation theory. Phys Chem Chem Phys 17:8407-15
Vilseck, Jonah Z; Kostal, Jakub; Tirado-Rives, Julian et al. (2015) Application of a BOSS-Gaussian interface for QM/MM simulations of Henry and methyl transfer reactions. J Comput Chem 36:2064-74
Lee, Won-Gil; Frey, Kathleen M; Gallardo-Macias, Ricardo et al. (2015) Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem Lett 25:4824-7
Dodda, Leela S; Vilseck, Jonah Z; Cutrona, Kara J et al. (2015) Evaluation of CM5 Charges for Nonaqueous Condensed-Phase Modeling. J Chem Theory Comput 11:4273-82
Robertson, Michael J; Tirado-Rives, Julian; Jorgensen, William L (2015) Improved Peptide and Protein Torsional Energetics with the OPLSAA Force Field. J Chem Theory Comput 11:3499-509

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