Novel heterocyclic hybrids of Thiophene clubbed 1,3,4-oxadiazoles targeting dihydrofolate reductase (DHFR): An in silico approach, molecular docking, ADMET studies, MM-GBSA assay and MD simulations

Abstract

Nowadays Antimicrobial resistance (AMR) is considered as one of the major global concern and has become the leading confront since bacteria is continuously involved in the development of resistance against the diversified class of antimicrobial agents. Therefore, there is an urgent demand to find the new inhibitors and targets to overcome this problem. Dihydrofolate reductase (DHFR) is considered as one of the key enzyme, which plays a major role in supporting bacterial growth and hence these inhibitors were found to be highly effective therapeutic agents in combating bacterial infections. In this present study, Thiophene-clubbed 1,3,4-oxadiazoles derivatives (T1–15) were designed as potential DHFR inhibitors by in silico approach. We investigated 99 compounds as potential inhibitors of DHFR and the top 15 compounds were further selected for molecular docking studies. By using Schrodinger Maestro all the compounds were subjected to molecular docking study against the DHFR target (PDB:1DG5). The compounds T1 (‐8.206 kcal/mol) and T2 (−7.701 kcal/mol) exhibited highest docking scores when compared to the standard Trimethoprim (−6.482) and adhered to Lipinski rule for drug likeness, ADMET and toxicity profile. The MM-GBSA analysis indicated stable binding free energies. MD simulations have been performed for compound T1 and Trimethoprim to determine the stability of the complex for 200 ns. Overall, this research lays the groundwork in the development of novel class of DHFR inhibitors.