Molecular docking studies of 1,3,4 -thiadiazoles as myeloperoxidase inhibitors

Abstract

Myeloperoxidase (MPO) is a heterodimeric, cationic and glycosylated haeme enzyme which gets released under increased oxidative stress producing neutrophil oxidant, hypochlorous acid having the capacity to modify various biomolecules by chlorination and/or oxidation of sulfhydryl groups in proteins causing their inactivation and promoting inflammatory tissue damage. Different levels of hypochlorus acid are used as a trait marker for prescribing the disorders e.g. atherosclerosis, rheumatoid arthritis, lung cancer, Immuno-reactivity. Mini library of 22500 2,5disubstituted 1,3,4 thiadiazoles were docked with Myeloperoxidase in order to identify the potent inhibitor against the enzyme. The chemical nature of the protein and ligands greatly influence the performance of docking process. Keeping this fact in view, critical evaluation of the performance was performed by GLIDE by HTVS, SP and XP. The ADME parameters by QIKPROP and protein-ligand binding free energies were calculated using the Prime/MM-GBSA module of Schrödinger.Both hydrogen bonding and hydrophobic interactions contributed significantly for its ligand binding and core influence the target site through prominent hydrophobic and charged interaction with the backbone and side chain residues in the target site that improves the affinity of the molecule. The compound selected as potent inhibitor is having minimum binding affinity, maximum GScore and minimum FlexX energy. The amino acids residues ASP98, ASP94, THR100 and GLU 102 in the MPO gene domain active site form hydrogen bonds with the ligand. Compounds 3350-5150 showed better interaction with haeme enzyme for further understanding of structures, reliability and Biomolecularactivityy in connection with oxidative stress induced disorders.