Molecular Recognition of Proteins and Ligand Design

Yale University, New Haven CT

Investigators

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Abstract

DESCRIPTION (provided by applicant): 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.