In Silico Development of Novel Benzofuran-1,3,4-Oxadiazoles as Lead Inhibitors of Polyketide Synthase 13.

Benzofuran and 1,3,4-oxadiazole are privileged and versatile heterocyclic pharmacophores which display a broad spectrum of biological and pharmacological therapeutic potential against a wide variety of diseases. This article reports in silico CADD (computer-aided drug design) and molecular hybridization approaches for the evaluation of the chemotherapeutic efficacy of 16 S-linked -phenyl acetamide moiety containing benzofuran-1,3,4-oxadiazole scaffolds . This virtual screening was carried out to discover and assess the chemotherapeutic efficacy of structural motifs as polyketide synthase 13 (Mtb Pks13) enzyme inhibitors. The CADD study results revealed that the benzofuran clubbed oxadiazole derivatives , , and showed excellent and remarkably significant binding energies against the Mtb Pks13 enzyme comparable with the standard benzofuran-based inhibitor. The best binding affinity scores were displayed by 1,3,4-oxadiazoles-based benzofuran scaffolds (-14.23 kcal/mol), (-14.82 kcal/mol), and (-14.11 kcal/mol), in comparison to the binding affinity score of the standard reference drug (-14.61 kcal/mol). 2,5-Dimethoxy moiety-based bromobenzofuran-oxadiazole derivative demonstrated the highest binding affinity score amongst the screened compounds, and was higher than the reference Pks13 inhibitor drug. The bindings of these three leads , , and were further confirmed by the MM-PBSA investigations in which they also exhibited strong bindings with the Pks13 of Mtb. Moreover, the stability analysis of these benzofuran-1,3,4-oxadiazoles in the active sites of the Pks13 enzyme was achieved through molecular dynamic (MD) simulations at 250 ns virtual simulation time, which indicated that these three in silico predicted bio-potent benzofuran tethered oxadiazole molecules , , and demonstrated stability with the active site of the Pks13 enzyme.