Combined Bioinformatics and Combinatorial Chemistry Tools to Locate Drug‐Able Anti‐TB Phytochemicals: A Cost‐Effective Platform for Natural Product‐Based Drug Discovery

Abstract

Based on extensive experimental studies, a huge number of phytochemicals showed potential activity against tuberculosis (TB) at a lower minimum inhibitory concentration (MIC) and fewer toxicity profiles. However, these promising drugs have not been able to convert from 'lead' to 'mainstream' due to inadequate drug-ability profiles. Thus, early drug-prospective analyses are required at the primary stage to accelerate natural-productbased drug discovery with limited resources and time. In the present study, we have selected seventy-three potential anti-TB phytochemicals (MIC value � 10 μg/mL) and assessed the drug-ability profiles using bioinformatics and combinatorial chemistry tools, systematically. Primarily, the molecular docking study was done against two putative drug targets, catalase-peroxidase enzyme (katG) and RNA polymerase subunit-β (rpoB) of Mycobacterium tuberculosis (Mtb) using AutoDock 4.2 software. Further, assessed the drug-ability score from Molsoft, toxicity profiles from ProTox, pharmacokinetics from SwisADME, hierarchical cluster analysis (HCA) by ChemMine tools and frontier molecular orbitals (FMOs) with Avogadro and structural activity relationships (SAR) analysis with ChemDraw 18.0 software. Above analyses indicated that, lower MIC exhibited anti-TB phytochemicals, abietane, 12-demethylmulticaulin exhibited poor docking and drug-ability scores, while tiliacorinine, 2-nortiliacorinine showed higher binding energy and drug-ability profiles. Overall, tiliacorinine, 2-nortiliacorinine, 7α-acetoxy-6β-hydroxyroyleanone (AHR), (2S)-naringenin and isovachhalcone were found as the most active and drug-able anti-TB candidates from 73 candidates. Phytochemicals are always a vital source of mainstream drugs, but the MIC value of a phytochemical is not sufficient for it to be promoted. An ideal drugability profile is therefore essential for achieving clinical success, where advanced bioinformatics tools help to assess and analyse that profile. Additionally, several natural pharmacophores found in existing anti-TB drugs in SAR analyses also provide crucial information for developing potential anti-TB drug. As a conclusion, combined bioinformatics and combinatorial chemistry are the most effective strategies to locate potent-cum-drug-able candidates in the current drug-development module.

Antimycobacterial Compound of Cynoglossum lanceolatum Forsk.: Bioassay Guided Isolation, Molecular Docking, Synthesis of Analogs, and a Plausible Mechanism of Action

“…AutoDock 4 (version 4.2.5) was used for docking analysis. The protein‐ligand docking complexes were visualized by BIOVIA Discovery Studio Visualizer v.19.1.0 [13,14] …”

“…Nuclear magnetic resonance (NMR) spectra were acquired using Bruker AV 400 (Bruker BioSpin, Rheinstetten, Germany) NMR spectrometers using (D 6 )DMSO as solvent. Chemical shifts (δ) for 1 H and 13 C-NMR spectra are expressed in ppm. EI-MS was recorded on Hewlett-Packard 1100.…”

“…Based on the antibacterial activity of the ethyl acetate partition, it (24 g) was further subjected to silica gel H column chromatography eluting with hexane containing increasing amounts of ethyl acetate to afford 19 major fractions (Fr. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Among the nineteen fractions, Fr.…”

“…Grey white powder, yield: 172 mg (58 %); 1 H-NMR (400 MHz, (D 6 )DMSO) δ: 10.32 (s, 2H, H-15), 8.51 (d, J = 2.5, 1H, H-6), 8.33 (d, J = 5.8, 1H, H-2), 7.41 (dd, J = 8.8, 2.5, 1H, H-13), 6.86 (dd, J = 14.6, 5.9, 1H, H-3), 4.22 (t, J = 6.3, 2H, H-8), 2.33 (d, J = 2.0, 2H, H-9). 13…”

“…The protein-ligand docking complexes were visualized by BIOVIA Discovery Studio Visualizer v.19.1.0. [13,14] In Vitro Enzymatic Assay Isolation, purification, and inhibition assay of Mtb KatG was performed as previously described. [15] The KatG activity was measured spectrophotometrically and quantified by the amount of undecomposed hydrogen peroxide in the reaction system.…”