Ligand Macromolecular Interactions In Drug Discovery PDF Download

Abstract: A wide array of molecular modeling tools was utilized to understand the underlying principles of ligand-macromolecular interactions and utilize them for drug discovery and design applications. A structure based virtual screening methodology was elucidated to target the viral cysteine protease SARS-3CL pro and identify "micromolar" hits for potential development of antiviral therapy. The initial hits were utilized in a similarity/substructure search to identify biologically active analogues which further helped in understanding the SAR of these series. A synthetic strategy was developed for generating structural analogues of one of the identified hits. On a broader perspective, the irreversible inactivation mechanism of cysteine proteases was explored through a novel quantum mechanics/molecular mechanics study on the inhibition of the cysteine protease cruzain by vinyl sulfone based Michael acceptors. Strategies for small molecule based inhibition of protein-protein interaction interfaces was studied using cross-docking based virtual screening against the Bcl-xL protein. Biological assay validation and compound evaluation was carried out to identify micromolar hits. Docking pose based pharmacophore models were developed to predict the concomitant binding of Bcl-xL inhibitors to the Drug site 2 of HSA. Ligand-refined homology model development, simulation and docking validation studies were performed for structure-based drug design initiatives against the L.major and L.donovani FPPS enzyme. Comparative protein structure analysis of parasitic FPPS enzymes were carried out to understand the differences in their protein structural topology.