Molecular Docking Suggests the Targets of Anti-Mycobacterial Natural Products

Abstract

Tuberculosis (TB) is a major global threat, mostly due to the development of antibiotic-resistant forms of Mycobacterium tuberculosis, the causal agent of the disease. Driven by the pressing need for new anti-mycobacterial agents several natural products (NPs) have been shown to have in vitro activities against M. tuberculosis. The utility of any NP as a drug lead is augmented when the anti-mycobacterial target(s) is unknown. To suggest these, we used a molecular reverse docking approach to predict the interactions of 53 selected anti-mycobacterial NPs against known “druggable” mycobacterial targets ClpP1P2, DprE1, InhA, KasA, PanK, PknB and Pks13. The docking scores/binding free energies were predicted and calculated using AutoDock Vina along with physicochemical and structural properties of the NPs, using PaDEL descriptors. These were compared to the established inhibitor (control) drugs for each mycobacterial target. The specific interactions of the bisbenzylisoquinoline alkaloids 2-nortiliacorinine, tiliacorine and 13′-bromotiliacorinine against the targets PknB and DprE1 (−11.4, −10.9 and −9.8 kcal·mol−1; −12.7, −10.9 and −10.3 kcal·mol−1, respectively) and the lignan α-cubebin and Pks13 (−11.0 kcal·mol−1) had significantly superior docking scores compared to controls. Our approach can be used to suggest predicted targets for the NP to be validated experimentally, but these in silico steps are likely to facilitate drug optimization.

Pyridine‐N‐Oxide Alkaloids from Allium stipitatum and Their Synthetic Disulfide Analogs as Potential Drug Candidates against Mycobacterium tuberculosis: A Molecular Docking, QSBAR, and ADMET Prediction Approach

“…Eight (8) conventional hydrogen bonds (distances between 1.93 and 2.55 Å), two π − σ bond, one π-sulphur (4.41 Å), 2 π-alkyl bonds (π-interaction with Val 25 and Met 155 at distances of 4.87 and 4.67 Å, respectively), two C-H bond with Val 95 and Asp 156 amino acid residues at distances of 3.28 and 3.36 Å, respectively, eleven Van der Waals, and one unfavourable acceptor and acceptor bond(2.71 Å between the aromatic C-O and ASP 156 amino acid residue) were observed. The binding scores from the validation docking were between -7.6 and -7.9 kcal/mol, and this was consistent with that obtained by Baptista et al (that is, -7.7 kcal/mol)[22].…”

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

“…The frontier molecular orbital (FMOs) theory was also employed to observe the kinetic stability/ flexibility of the selected potential compounds through the energy gap (eV) of HOMO‐LUMO orbitals [12,22,35] . Consequently, a number of potential phytochemicals with standard anti‐TB drugs were analyzed using Avogadro‐ORCA 4.2 suits [40,57] . Before HOMO and LUMO analysis, geometry optimization and energy minimization in a universal force field (UFF) with the steepest descent algorithms were employed.…”

“…[12,22,35] Consequently, a number of potential phytochemicals with standard anti-TB drugs were analyzed using Avogadro-ORCA 4.2 suits. [40,57] Before HOMO and LUMO analysis, geometry optimization and energy minimization in a universal force field (UFF) with the steepest descent algorithms were employed.…”

Integrating network pharmacology and in vitro experiment to investigate the protective effects of semen cuscutae flavonoid on sertoli cells and blood-testis barrier in male infertility under heat stress

“…Network pharmacology is an approach to explore the mechanism of action of drugs by constructing the interrelated network of "drugs-target-diseases", and provides new methods for studying the complex pharmacological mechanisms of Chinese herbs [12]. Network pharmacology systematically combines the biological and the drug networks to comprehensively analyze the mechanism of Chinese herbs and prescribe them in the treatment, which is similar to the "overall concept" of TCM theory [13]. In the current study, we employed network pharmacology to explore the targets and signaling pathways of SCF and veri ed them using in vitro experiments to clarify the mechanism of action of Semen cuscutae in the treatment of MI, provide a theoretical basis for the clinical application and scienti c research of Semen cuscutae, and also provide insights for the drug research and development for MI.…”