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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Trivedi-Parmar, Vinay; Jorgensen, William L (2018) Advances and Insights for Small Molecule Inhibition of Macrophage Migration Inhibitory Factor. J Med Chem 61:8104-8119
Trivedi-Parmar, Vinay; Robertson, Michael J; Cisneros, José A et al. (2018) Optimization of Pyrazoles as Phenol Surrogates to Yield Potent Inhibitors of Macrophage Migration Inhibitory Factor. ChemMedChem 13:1092-1097
Cabeza de Vaca, Israel; Qian, Yue; Vilseck, Jonah Z et al. (2018) Enhanced Monte Carlo Methods for Modeling Proteins Including Computation of Absolute Free Energies of Binding. J Chem Theory Comput 14:3279-3288
Dodda, Leela S; Tirado-Rives, Julian; Jorgensen, William L (2018) Unbinding Dynamics of Non-Nucleoside Inhibitors from HIV-1 Reverse Transcriptase. J Phys Chem B :
Dawson, Thomas K; Dziedzic, Pawel; Robertson, Michael J et al. (2017) Adding a Hydrogen Bond May Not Help: Naphthyridinone vs Quinoline Inhibitors of Macrophage Migration Inhibitory Factor. ACS Med Chem Lett 8:1287-1291
Chan, Albert H; Lee, Won-Gil; Spasov, Krasimir A et al. (2017) Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography. Proc Natl Acad Sci U S A 114:9725-9730
Dodda, Leela S; Vilseck, Jonah Z; Tirado-Rives, Julian et al. (2017) 1.14*CM1A-LBCC: Localized Bond-Charge Corrected CM1A Charges for Condensed-Phase Simulations. J Phys Chem B 121:3864-3870
Robertson, Michael J; Tirado-Rives, Julian; Jorgensen, William L (2017) Improved Treatment of Nucleosides and Nucleotides in the OPLS-AA Force Field. Chem Phys Lett 683:276-280
Yan, Xin Cindy; Robertson, Michael J; Tirado-Rives, Julian et al. (2017) Improved Description of Sulfur Charge Anisotropy in OPLS Force Fields: Model Development and Parameterization. J Phys Chem B 121:6626-6636
Dodda, Leela S; Cabeza de Vaca, Israel; Tirado-Rives, Julian et al. (2017) LigParGen web server: an automatic OPLS-AA parameter generator for organic ligands. Nucleic Acids Res 45:W331-W336

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