CONSERVED WATER MIMIC INHIBITOR DESIGN FOR hIMPDH (INOSINE MONOPHOSPHATE DEHYDROGENASE): MD SIMULATION AND DOCKING STUDIES OF IMP-ANALOGS

Inosine Monophosphate Dehydrogenase (IMPDH) plays a very important role in Guanosine Monophosphate (GMP) biosynthesis. Type I hIMPDH is expressed at lower levels in all cells, whereas type II is especially observed in acute myelogenous leukemia, chronic myelogenous leukemia cancer cells, so it is thought to be an active target for leukemic drug design. MD-simulation studies of the solvated modeled structure of hIMPDH (PDB Id: 1B3O) in the presence of NAD⁺ have revealed some interesting feature on the role of some conserved water molecules in the binding of IMP to the enzyme. Based on H-bonding interaction of IMP with Asp 364, Arg 322, Asp 274, Cys 331 and Asn 303 residues in the X-ray and simulated structures, and the recognition dynamics of O₂’ and O₃’ ribose hydroxyl groups (of IMP) with the conserved water molecules, we have modified the hydroxyl group of IMP and modeled a few number of derivatives. Optimization of ligand structures, followed by docking in enzyme, solvation, energy minimization of the protein-ligand complexes and their successive all atoms simulation studies have been made up to 5 ns. After critical investigation of different snapshots, the stereochemical quality, binding affinity/energy of the modified ligand is calculated and have screened three IMP-analogs (modified at O₂’ and O₃’ ribose oxygen), which can also effectively interact with the residues of the mononucleotide binding pocket and may thought to act as inhibitor for IMPDH. The drug-likeness and drug score of the modeled compounds are observed to be better.