In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis

Abstract

The alarming increase in multi- and extensively drug-resistant (MDR and XDR) strains of Mycobacterium tuberculosis (MTB) has triggered the scientific community to search for novel, effective, and safer therapeutics. To this end, a series of 3,5-disubstituted-1,2,4-oxadiazole derivatives ( 3a–3i ) were tested against H37Rv, MDR and XDR strains of MTB. Of which, compound 3a with para-trifluorophenyl substituted oxadiazole showed excellent activity against the susceptible H37Rv and MDR-MTB strain with a MIC values of 8 and 16 µg/ml, respectively. To understand the mechanism of action of these compounds ( 3a–3i ) and identify their putative drug target, molecular docking and dynamics studies were employed against a panel of 20 mycobacterial enzymes reported to be essential for mycobacterial growth and survival. These computational studies revealed polyketide synthase (Pks13) enzyme as the putative target. Moreover, in silico ADMET predictions showed satisfactory properties for these compounds, collectively, making them, particularly compound 3a , promising leads worthy of further optimisation.

Phytochemical, Cytotoxicity, and Antimycobacterial Activity Evaluation of Extracts and Compounds from the Stem Bark of Albizia coriaria Welw ex. Oliver

“…Like in our study, the ligands showed comparable binding affinities with the standard drugs. In contrast to our study, the main stabilizing interactions between the compounds and the enzyme were π - π interactions with the aromatic amino acid residues Phe1590, Tyr1637, Phe1585, Tyr1674, Phe1670, and the catalytic His1699 with intermittent hydrogen bonding with Ser1636 and Asn1640 [ 38 ]. In another study, five new benzofuran derivatives were reported to have sufficient binding affinity for the pks-13 synthase with an alternative binding mode to the active site [ 42 ].…”

“…The interactions of the mycolic acids with other cell wall components make the mycobacterial cell walls very unique and contribute to the challenges associated with mycobacterium especially its pathogenesis, persistence, and chemotherapy. Given the critical role of mycolic acids in mycobacterium cell viability and pathogenesis, enzymes involved in mycolic acids biosynthesis, such as pks-13 present novel targets for drug development [ 38 ]. On the other hand, mycobacterial ATP synthase is another validated drug target and compounds inhibiting this enzyme are promising drug candidates [ 39 ].…”

“…For example, 3′,8,8′-trimethoxy-3-piperidyl-2,2′-binaphthalene-1,1′,4,4′-tetrone and l-leucine, N -(2-chloroethoxycarbonyl)- N -methyl-, pentadecyl ester blocked the pks-13 and ATP synthase with binding energies of -26.8626 and -28.7742 (kcal/mol). In a related study to evaluate the antimycobacterial activity of a series of 3,5-disubstituted-1,2,4-oxadiazole derivatives, pks-13 was used as a putative molecular target [ 38 ]. Like in our study, the ligands showed comparable binding affinities with the standard drugs.…”

Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives

“…The selected protein crystal structures were prepared, solvated and minimized, as previously described [ 64 , 65 , 66 ], in order to remove any potential artifacts caused by crystal packing. The binding sites were then determined, and all co-crystallized ligands were extracted and redocked into their appropriate binding sites.…”

“…The value of the correlation coefficient ( r ) determines the strength of association between the two sets of variables. Generally, a value of | r | between 0.1–0.3 indicates a small association, 0.3–0.5 is medium, and 0.5–1.0 indicates a large association [ 66 ]. Furthermore, this enzyme showed another high correlation with LigScore1 ( r = −0.63).…”