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AbstractThe Wnt/β-catenin pathway plays an important regulatory role in cancer signaling and cell regenerative mechanisms. Its suppression has long been considered as an important challenge of anticancer treatment and management. The poly(ADP-ribose) polymerase (PARP) family represented as a new class of therapeutic targets with diverse potential disease indications. Tankyrase (TNKS) is considered to be a potential target for the intervention of various cancers. The main objective of the work is to explore the molecular and quantum mechanics of the drug-like compounds and to identify the potential inhibitors for TNKS protein using the structure and ligand-based virtual screening from several databases and to explore the binding pocket and interactions of active residues. The screened compounds were further filtered using binding-free energy calculation and molecular dynamics simulation studies. The results have provided a strong molecular knowledge of TNKS and offered top hit potent inhibitors. The identified lead compounds LC_40781, LC_40777, LC_39767, LC_8346, NCI_682438, and NCI_721141 were observed to have potent activity against TNKS protein. The hydrogen bonding of compounds with Asp1198, His1201, Tyr1203 in TNKS1 and Gly1032, Ser1068 in TNKS2 are the key interactions plays a major role in binding energy. Therefore, the outcome of the study would help for further validation and provides valuable information to guide the future TNKS-specific inhibitor designing.Communicated by Ramaswamy H. Sarma

Vitamin D is a key signalling molecule that plays a vital role in the regulation of calcium phosphate homeostasis and bone remodelling. The circulating biologically active form of vitamin D is regulated by the catabolic mechanism of cytochrome P450 24-hydroxylase (CYP24A1) enzyme. The over-expression of CYP24A1 negatively regulates the vitamin D level, which is the causative agent of chronic kidney disease, osteoporosis and several types of cancers. In this study, we found three potential lead molecules adverse to CYP24A1 through structure-based, atom-based pharmacophore and e-pharmacophore-based screening methods. Analysis was done by bioinformatics methods and tools like binding affinity (binding free energy), chemical reactivity (DFT studies) and molecular dynamics simulation (protein–ligand stability). Combined computational investigation showed that the compounds NCI_95001, NCI_382818 and UNPD_141613 may have inhibitory effects against the CYP24A1 protein.