Abstract
Schizophrenia is a complex, chronic mental disorder, affecting about 21 million people worldwide. It is characterized by symptoms, including distortions in thinking, perception, emotions, disorganized speech, sense of self and behavior. Recently, a numbers of marketed drugs for Schizophrenia are available against dopamine D2 and serotonin 5-HT2A receptors. Here, we docked Olanzapine derivatives (collected from literature) with 5-HT2A Receptor using the program AutoDock 4.2. The docked protein inhibitor complex structure was optimized using molecular dynamics simulation for 5ps with the CHARMM-22 force field using NAMD (NAnoscale Molecular Dynamics program) incorporated in visual molecular dynamics (VMD 1.9.2) and then evaluating the stability of complex structure by calculating RMSD values. NAMD is a parallel, object-oriented molecular dynamics code designed for high-performance simulation of large biomolecular systems. A quantitative structure activity relationship (QSAR) model was built using energy-based descriptors as independent variable and pKi value as dependent variable of eleven known Olanzapine derivatives with 5-HT2A Receptor, yielding correlation coefficient r2 of 0.63861. The predictive performance of QSAR model was assessed using different crossvalidation procedures. Our results suggest that a ligand-receptor binding interaction for 5-HT2A receptor using a QSAR model is promising approach to design more potent 5-HT2A receptor inhibitors prior to their synthesis.
Highlights
In today world, most of the people are suffering from mental disorder due to many reasons like environmental factors, genetic factors [1] and misbalancing in chemical transmission
Schizophrenia etiology indicates that many factors are involved, namely genetic factors, [5, 6] alterations in chemical transmission [7], Obstetrical complications [8] and Viral infections [9]
We docked experimentally verified 11 Olanzapine -based inhibitors having inhibitory value pKi with 5-HT2A receptor using AutoDock 4.2, which resulted in energy-based descriptors
Summary
Most of the people are suffering from mental disorder due to many reasons like environmental factors, genetic factors [1] and misbalancing in chemical transmission. We docked experimentally verified 11 Olanzapine -based inhibitors having inhibitory value pKi with 5-HT2A receptor using AutoDock 4.2, which resulted in energy-based descriptors. Methodology: Protein target structure: The 3D coordinates of the crystal structure of the LSD-bound 5HT2B retrieved from Protein Databank (http://www.rcsb.org/) The goal of ligand—protein docking is to predict the predominant binding model(s) of a ligand with a protein of known three-dimensional structure [21]. Docking of eleven olanzapine derivatives screened from literature against 5-HT2A Receptor structure were done using molecular docking program AutoDock [22]. In docking studies of olanzapine atoms, and all atoms were calculated by taking structure with derivatives with 5-HT2A Receptor, best autodock score was used reference conformation points.
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