In Vitro and In Silico Evaluations of Anti-Mycobacterium tuberculosis Activity of Benzohydrazones Compounds

The 3-hydroquinate synthase (DHQase) is an enzyme that catalyzes the third step of the shikimate pathway in <i>Mycobacterium tuberculosis</i> (MTB), by converting 3-dehydroquinate into 3-dehydroshikimate. In this study, the novel inhibitors of DHQase from MTB was identified using in silico approach. The crystal structure of DHQase bound to 1,3,4-trihydroxy-5-(3-phenoxypropyl)-cyclohexane-1-carboxylic acid (CA) obtained from the Protein Data Bank (PDB ID: 3N76). The structure prepared through energy minimization and structure optimization. A total of 9699 compounds obtained from Zinc and PubChem databases capable of binding to DHQase and subjected to virtual screening through Lipinski’s rule of five and molecular docking analysis. Eight (8) compounds with good binding energies, ranged between ─8.99 to ─8.39kcal/mol were selected, better than the binding energy of ─4.93kcal/mol for CA and further filtered for pharmacokinetic properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity or ADMET). Five compounds (ZINC14981770, ZINC14741224, ZINC14743698, ZINC13165465, and ZINC8442077) which had desirable pharmacokinetic properties selected for molecular dynamic (MD) simulation and molecular generalized born surface area (MM-GBSA) analyses. The results of the analyses showed that all the compounds formed stable and rigid complexes after the 50ns MD simulation and also had a lower binding as compared to CA. Therefore, these compounds considered as good inhibitors of MTB after in vitro and in vivo validation.”

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BIOAKTIVITAS DAN STUDI IN SILICO SENYAWA TURUNAN N’-BENZOYLISONICOTINOHYDRAZIDE (4-methyl, 4-chloro dan 3,5-dinitro) PADA Mycobacterium Tuberculosis (H37RV) BAKTERI GRAM POSITIF SERTA BAKTERI GRAM NEGATIF

Pharmacoscript ◽

10.36423/pharmacoscript.v2i1.239 ◽

2019 ◽

Vol 2 (1) ◽

pp. 37-48

Author(s):

Ruswanto Ruswanto

Keyword(s):

Mycobacterium Tuberculosis ◽

Binding Affinity ◽

In Silico ◽

Tuberculosis H37rv ◽

Mycobacterium Tuberculosis H37rv ◽

Microtiter Assay

Isoniazid merupakan obat antituberkulosis yang memiliki aktivitas antimikobakterial yang baik yang bekerja secara aktif dengan menghambat biosintesis asam mikolat. Telah dilakukan pengujian In Vitro pada senyawa N’-(4-Methylbenzoyl) Isonicotinohydrazide N’-(4-Chlorobenzoyl) Isonicotinohydrazide dan N’-(3,5-Dinitrobenzoyl) Isonicotinohydrazide terhadap Mycobacterium tuberculosis H37Rv, bakteri gram positif serta bakteri gram negatif dengan menggunakan metode sumuran dan pada pengujian Mycobacterium tuberculosis H37Rv menggunakan metode REMA (Resazurin Microtiter Assay). Didapat nilai MIC terbaik pada senyawa N’-(3,5-Dinitrobenzoyl) Isonicotinohydrazide memiliki potensi tinggi sebagai antibakteri dengan nilai MIC 0,169 ppm terhadap bakteri e.colli. Ketiga senyawa yang diujikan pada Mycobacterium tuberculosis H37Rv memiliki kemampuan sebagai anti tuberkulosis tetapi isoniazid lebih baik dari senyawa uji. Senyawa N’-(3,5-Dinitrobenzoyl) Isonicotinohydrazide di dockingkan pada reseptor 1KZN memiliki binding affinity yang lebih kecil dibandingkan senyawa pembanding yaitu isoniazid sebesar -6,89 kkal/mol.

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in silico Design, ADME Prediction, Molecular Docking, Synthesis of Novel Triazoles, Indazoles & Aminopyridines and in vitro Evaluation of Antitubercular Activity

Asian Journal of Chemistry ◽

10.14233/ajchem.2020.22790 ◽

2020 ◽

Vol 32 (11) ◽

pp. 2713-2721

Author(s):

S. Triveni ◽

C. Naresh Babu ◽

E. Bhargav ◽

M. Vijaya Jyothi

Keyword(s):

Mycobacterium Tuberculosis ◽

Molecular Docking ◽

Drug Design ◽

In Silico ◽

Antitubercular Activity ◽

Docking Studies ◽

Luciferase Reporter ◽

Assay Method ◽

Adme Prediction

To design and synthesize novel triazoles, indazoles and aminopyridines from various (thiophene-2-yl)prop-2-en-1-one derivatives as antitubercular leads by in silico and in vitro methods. in silco Drug design, ADME prediction and molecular docking studies were performed to assess drug likeliness and antitubercular potential of all 30 novel triazoles, indazoles and aminopyridines. in silico Drug design studies revealed that the synthetic routes applied were appropriate according to the calculations of Swiss-ADME that measure synthetic accessibility. Most of the synthesized compounds found to have considerable binding score with enoyl ACP reductase enzyme of Mycobacterium tuberculosis. All the synthesized compounds were evaluated for antitubercular potential against Drug Resistant Mycobacterium tuberculosis H37Rv strain by Luciferase reporter assay method. Most of the synthesized compounds exhibited remarkable antitubercular potential against resistant strain.

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In silico drug discovery strategies identified ADMET properties of decoquinate RMB041 and its potential drug targets against Mycobacterium Tuberculosis

10.1101/2021.11.17.469062 ◽

2021 ◽

Author(s):

Kirsten Elke Knoll ◽

Mietha M. van der Walt ◽

Du toit Loots

Keyword(s):

Mycobacterium Tuberculosis ◽

In Silico ◽

Drug Targets ◽

Cellular Response ◽

Molecular Mechanisms ◽

Antimicrobial Agents ◽

Screening Methods ◽

Discovery Studio ◽

Optimal Drug

The highly adaptive cellular response of Mycobacterium tuberculosis to various antibiotics and the high costs for clinical trials, hampers the development of novel antimicrobial agents with improved efficacy and safety. Subsequently, in silico drug screening methods are more commonly being used for the discovery and development of drugs, and have been proven useful for predicting the pharmacokinetics, toxicities, and targets, of prospective new antimicrobial agents. In this investigation, we used a reversed target fishing approach to determine potential hit targets and their possible interactions between M. tuberculosis and decoquinate RMB041, a propitious new antituberculosis compound. Two of the thirteen identified targets, Cyp130 and BlaI, were strongly proposed as optimal drug-targets for dormant M. tuberculosis, of which the first showed the highest comparative binding affinity to decoquinate RMB041. The metabolic pathways associated to the selected target proteins were compared to previously published molecular mechanisms of decoquinate RMB041 against M. tuberculosis, whereby we confirmed disrupted metabolism of proteins, cell wall components, and DNA. We also described the steps within these pathways that are inhibited and elaborated on decoquinate RMB041's activity against dormant M. tuberculosis. This compound has previously showed promising in vitro safety and good oral bioavailability, which were both supported by this in silico study. The pharmacokinetic properties and toxicity of this compound were predicted and investigated using the online tools pkCSM and SwissADME, and Discovery Studio software, which furthermore supports previous safety and bioavailability characteristics of decoquinate RMB041 for use as an antimycobacterial medication.

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