in silico Binding Mode Analysis (Molecular Docking Studies) and Absorption, Distribution, Metabolism and Excretion Prediction of Some Novel Inhibitors of Aurora Kinase A in Clinical Trials

摘要

The inhibition of Aurora kinase A is considered to be one of the most promising therapeutic targets for the treatment of cancer. To gain insight into the structural requirements for effective binding and inhibiting the enzyme Aurora kinase A, molecular dockins study was carried out by using the potent Aurora kinase A inhibitors (AKAIs) that are currently under clinical trials by employing Glide module of Schrodinger software. Prime MM-GBSA approach was used to study the free energy of binding of these AKIs with the enzyme. Binding mode analysis indicated that a molecule should occupy both ATP binding site (forming essential hydrogen bonding interaction with crucial amino acid residue such as Ala213) as well as allosteric binding cleft (forming hydrogen bonding interaction with amino acid residues Lys162 and Glu181) for exhibiting optimum affinity as well as selectivity towards Aurora kinase A. Further, ADME properties of these study compounds were calculated to get better insight into the physicochemical requirements for effective binding of ligands with Aurora kinase A and also to evaluate their drug-like acceptability which was found to be in the ranges predicted by QikProp module of Schrodinger software for 95 % of known oral drugs. Results confirm the potential of the study which could be useful for the design of new potent inhibitors of Aurora kinase A as possible anticancer agents.