02536nas a2200205   4500008004100000022001400041245012100055210006900176260000800245520178100253653002102034653003402055653001302089653002402102653001502126100001802141700002202159700002102181856012802202       2019                        eng d  a0887-358500aMolecular basis of drug resistance in smoothened receptor: an in silico study of protein resistivity and specificity0 aMolecular basis of drug resistance in smoothened receptor an in   cOCT3 a<p>Smoothened (SMO) antagonist Vismodegib effectively inhibits the Hedgehog pathway in proliferating cancer cells. In early stage of treatment, Vismodegib exhibited promising outcomes to regress the tumors cells, but ultimately relapsed due to the drug resistive mutations in SMO mostly occurring before (primary mutations G497W) or after (acquired mutations D473H/Y) anti-SMO therapy. This study investigates the unprecedented insights of structural and functional mechanism hindering the binding of Vismodegib with sensitive and resistant mutant variants of SMO (SMOMut). Along with the basic dynamic understanding of Vismodegib-SMO complexes, network propagation theory based on heat diffusion principles is first time applied here to identify the modules of residues influenced by the individual mutations. The allosteric modulation by GLY497 residue in Vismodegib bound SMO wild-type (SMOWT) conformation depicts the interconnections of intermediate residues of SMO with the atom of Vismodegib and identify two important motifs (E-X-P-L) and (Q-A-N-V-T-I-G) mediating this allosteric regulation. In this study a novel computational framework based on the heat diffusion principle is also developed, which identify significant residues of allosteric site causing drug resistivity in SMOMut. This framework could also be useful for assessing the potential allosteric sites of different other proteins. Moreover, previously reported novel inhibitor ``ZINC12368305,'' which is proven to make an energetically favorable complex with SMOWT is chosen as a control sample to assess the impact of receptor mutation on its binding and subsequently identify the important factors that govern binding disparity between Vismodegib and ZINC12368305 bound SMOWT/Mut conformations.</p>
10aallosteric sites10amolecular dynamics simulation10aMutation10asmoothened receptor10aVismodegib1 aSinha, Noopur1 aChowdhury, Saikat1 aSarkar, Ram, Rup  uhttps://library.ncl.res.in/content/molecular-basis-drug-resistance-smoothened-receptor-silico-study-protein-resistivity-and