Targeting Catechol-O-Methyl Transferase (COMT) Inhibitors for Schizophrenia:An Approach to Target Validation and Rational Drug Design
Schizophrenia is a disorder of abnormal neurodevelopment, with minor physical anomalies, neurological soft signs, and abnormalities of brain structure and functions. It is estimated that one percent of the worlds population is suffering from this disease. Extensive data recommend that genetic abnormalities of dopamine function are well-known features of schizophrenia that may play a unique role for catechol-O-methyl transferase (COMT) in dopamine-mediated prefrontal information processing in working memory. In this work, we describe a structure- based design approach that uses three-dimensional modeling of COMT. The modeled COMT structure was docked with twenty two inhibitors. The calculated binding energies from the docking analysis were also performed. The 7,8-dihydroxyflavone ligand was fitted to this site on membrane-bound COMT (MB-COMT) and soluble COMT (S-COMT) judging by docking studies, forming hydrogen bonds principally with the Lys144 residues. We have identified the toxicity using zebrafish model with the molecule (7,8-dihydroxyflavone). During the toxicity assay, no abnormality was found in embryonic development of zebrafish. So, it indicates that 7,8-dihydroxyflavone has no toxic effect on zebrafish larvae. So, we are very hopeful that this molecule may be a good drug candidate for future; however, more studies are required in this relation.
Keywords: Catechol-O-methyl transferase (COMT), Schizophrenia, Rational drug design, Target validation, Docking, Zebrafish
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