Pharmacophore Mapping Approach for Drug Target Identification: A Chemical Synthesis and in Silico Study on Novel Thiadiazole Compounds.

INTRODUCTION: Compounds containing thiadiazole moiety are cognized to possess with variety of clinical and therapeutic activity. Finding a suitable drug target for newly synthesized compounds remain a major bottle neck in current high throughout medicinal chemistry era.

AIM: To effectively synthesize di substituted thiadiazole compounds and demonstrate drug target identification using an in silico pharmacophore probing approach. Moreover, we also aim to validate the suitability of identified drug target.

MATERIALS AND METHODS: A cost-effective and environmental friendly chemical synthesis scheme for production of di substituted thiadiazole compounds was employed. Target identification was conducted by Pharmmapper software. Validation was accomplished by performing molecular docking and further Molecular Hydrophobic Potential (MHP) analysis.

RESULTS: Pharmacophore probing base approach identified hepatocyte growth factor receptor (c-Met) as a suitable biological target for newly synthesized compounds. Binding free energy values indicate that compound 4b, 4e, 4g and 4h has tremendous potential to be further used as lead compound to design selective inhibitors of c-Met receptor. MHP data from current study supports the possibility that hydrophobic contacts might act as major factor stabilizing thiadiazole- c-Met complex. Moreover, in silico observations of current study are in absolute accordance with previously described in vitro and crystallographic analysis.

CONCLUSION: We demonstrate that thiadiazole compounds synthesized in current investigation has high potential to act in modulation of hepatocyte growth factor receptor (c-Met) activity and thereby act as putative therapeutic agent in cancer therapy.