Prediction of binding affinity to hPXR by ELR methods

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to develop a portal which can be added to a fully automated drug design system that screens out inefficient and/or toxic therapeutic agents by calculating binding affinities of potential therapeutic agents to a human pregnane X receptor (hPXR), which is a known initiator of metabolism by cytochrome 450. With the available crystal structure of hPXR and experimentally obtained pharmaceutical activity, computational methods can be calibrated to predict binding affinities and hence pharmaceutical activities of previously untested potential therapeutic agents. A computational method used for this research, an extended linear response method, will also be compared to a more rigorous free energy perturbation method. The results obtained by methods described in this proposal will be combined with tools developed in the Jorgensen laboratory to implement into a fully automated drug design system. Studies proposed here will provide insight into the metabolism, efficiency, and toxicity of various therapeutic agents which can be applied in the discovery and development of a variety of drugs to treat ailments from arthritis to ulcers.