Integrated use of ligand and structure-based virtual screening, molecular dynamics, free energy calculation and ADME prediction for the identification of potential PTP1B inhibitors
Bharti Devi, Sumukh Satyanarayana Vasishta, Bhanuranjan Das, Anurag T. K. Baidya, Rahul Salmon Rampa, Manoj Kumar Mahapatra, Rajnish Kumar
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引用次数: 0
Abstract
Protein tyrosine phosphatases (PTPs) are the group of enzymes that control both cellular activity and the dephosphorylation of tyrosine (Tyr)-phosphorylated proteins. Dysregulation of PTP1B has contributed to numerous diseases including Diabetes Mellitus, Alzheimer’s disease, and obesity rendering PTP1B as a legitimate target for therapeutic applications. It is highly challenging to target this enzyme because of its highly conserved and positively charged active-site pocket motivating researchers to find novel lead compounds against it. The present work makes use of an integrated approach combining ligand-based and structure-based virtual screening to find hit compounds targeting PTP1B. Initially, pharmacophore modeling was performed to find common features like two hydrogen bond acceptors, an aromatic ring and one hydrogen bond donor from the potent PTP1B inhibitors. The dataset of compounds matching with the common pharmacophoric features was filtered to remove Pan-Assay Interference substructure and to match the Lipinski criteria. Then, compounds were further prioritized using molecular docking and top fifty compounds with good binding affinity were selected for absorption, distribution, metabolism, and excretion (ADME) predictions. The top five compounds with high solubility, absorption and permeability holding score of − 10 to − 9.3 kcal/mol along with Ertiprotafib were submitted to all-atom molecular dynamic (MD) studies. The MD studies and binding free energy calculations showed that compound M4, M5 and M8 were having better binding affinity for PTP1B enzyme with ∆Gtotal score of − 24.25, − 31.47 and − 33.81 kcal/mol respectively than other compounds indicating that compound M8 could be a suitable lead compound as PTP1B inhibitor.
期刊介绍:
Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including:
combinatorial chemistry and parallel synthesis;
small molecule libraries;
microwave synthesis;
flow synthesis;
fluorous synthesis;
diversity oriented synthesis (DOS);
nanoreactors;
click chemistry;
multiplex technologies;
fragment- and ligand-based design;
structure/function/SAR;
computational chemistry and molecular design;
chemoinformatics;
screening techniques and screening interfaces;
analytical and purification methods;
robotics, automation and miniaturization;
targeted libraries;
display libraries;
peptides and peptoids;
proteins;
oligonucleotides;
carbohydrates;
natural diversity;
new methods of library formulation and deconvolution;
directed evolution, origin of life and recombination;
search techniques, landscapes, random chemistry and more;