Gall bladder cancer (GBC) is an aggressive and most common malignancy of biliary tract lacking effective treatment due to unavailability of suitable biomarkers and therapeutics. SMAD4 is an essential mediator of transforming growth factor-β pathway involved in various cellular processes like growth, differentiation and apoptosis and also recognized as therapeutic target for GBC and other gastrointestinal tract cancers. In the present study, 3D structure of SMAD4 mutants was optimized through molecular dynamics simulation (MDS) along with wildtype. Furthermore, binding site of protein was predicted through hybrid approach and structural based virtual screening against two drug libraries was performed followed by docking. MDS of top docking score protein–ligand complexes were carried, and binding free energy was rescored. Two potential inhibitors, namely ZINC2098840 and ZINC8789167, were screened that displayed higher binding affinity towards mutant proteins compared with wildtype and both hydrophilic as well as hydrophobic interactions play a crucial role during protein–ligand binding. Current study identified novel and potent inhibitors of SMAD4 mutant that could be used as a drug candidate for the development of personalized medicine for gall bladder and other associated cancers.

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