Computational Chemistry Section

Diabetes, Digestive, Kidney Diseases

Investigators

Abstract

The aim of the Computational Chemistry Section within the Chemical Biology Core Facility is to provide molecular modeling support to partnerships established within NIDDK chemical and biological laboratories. The goal of these partnerships is the discovery of new medicinal agents with therapeutic potential. Utilizing state-of-the-art methods in computational chemistry, the Section was created in late 2004 and has been evolving to make available numerous resources to support laboratories within the Institute. More specifically, the laboratory now has in place the required infrastructure and the expertise necessary to provide structure-based and ligand-based drug design by performing sequence analysis, homology modeling, molecular dynamics simulations, development of ligand-protein interaction models, QSAR models, generation of virtual libraries and virtual screening of custom made or commercially available libraries. In particular, research within the group has been instrumental in the discovery that specific conformational requirements are necessary for locked nucleotide analogues to be recognized by the P2Y6 receptor. In addition, molecular dynamics results suggest that specific conformational changes take place within the extracellular region of the receptor subsequent to agonist binding. In an effort to identify structural features responsible for increased inhibitory capabilities of adenine nucleotide analogues towards the P2Y1 receptor, a CoMFA approach (comparative molecular field analysis) combined with a structure-based model has been applied to the data from an inhibition assay. Results are currently being summarized in a manuscript to be submitted shortly. Molecular dynamics simulations are also being performed on the TRH-R1 and TRH-R2 receptors embedded in a hydrated phospholipids bilayer to further our understanding of the binding modes and specificity of various ligands to the receptors. Mutated receptors are undergoing molecular dynamics simulations to help in the interpretation of experimental results on differential basal activities of various mutant receptors. The TRH-R1 receptor is also being subjected to a 3D database virtual screen of commercially available compounds (2.7M) to help identify peptidomimetics that could serve as either agonists or antagonists of the membrane receptor. The TSH receptor is also being subjected to molecular dynamics simulations and in silico docking to help in the understanding of the binding modes of peptidomimetics to the transmembrane region of the receptor. Anchored in a collaboration with the Receptors and Hormone Action Section, this works contributes to the first evidence that low molecular weight ligands bind within the helical bundle of glycoprotein hormone receptors.