Molecular dynamics simulations, essential dynamics and MMPBSA to evaluate natural compounds as potential inhibitors for AccD6, a key drug target in the fatty acid biosynthesis pathway in Mycobacterium tuberculosis

Abstract

Antibiotic resistance in Mycobacterium tuberculosis, the primary causative agent of the tuberculosis disease is an ever growing threat especially in developing and underdeveloped countries. Isoniazid is a commonly used first line anti-tuberculosis drug used during the first phase of tuberculosis treatment. However, due to its improper use, many strains of Mycobacterium tuberculosis have acquired resistance to the drug. Advancements in next generation sequencing technologies, such as transcriptomics have paved way for identifying alternative drug targets based on the differential expression pattern of genes. Therefore, this study makes use of RNA-Seq data of Mycobacterium tuberculosis isolates treated with different concentrations of isoniazid to identify genes that can be proposed as drug targets. From the differential expression analysis, it was observed that four genes were significantly upregulated under all the conditions. Among the four genes, accD6 was selected as the drug target for virtual screening and molecular dynamics studies, because of its role in fatty acid elongation and contribution to the synthesis of mycolic acids. The protein-protein interaction network and gene ontology based functional enrichment studies show an enrichment in fatty acid biosynthesis related pathways. Furthermore, virtual screening studies successfully screened the top three natural inhibitor molecules with satisfactory ADME properties and a better glide score than the reference compound, NCI-172033. The trajectory analysis, essential dynamics studies and MMPBSA analysis, concluded that among the hit molecules, NPC41982, a thiazole derivative showed the most promising results and can be considered as a potential drug candidate.