Docking and molecular dynamic study of isoniazid derivatives as anti-tuberculosis drug candidate

doi:10.1016/j.cdc.2021.100647

Chemical Data Collections

Volume 32, April 2021, 100647

https://doi.org/10.1016/j.cdc.2021.100647 Get rights and content

Abstract

In this research, we have designed four isoniazid derivatives, i.e., isonicotinohydrazide (1-isonicotinoyl semicarbazide, 1-thiosemi isonicotinoyl carbazide, N '-(1, 3-dimethyl-1 h-pyrazole-5-carbonyl) isonicotino hydrazide, and N '-(1,2,3- 4-thiadiazole-carbonyl) isonicotinohydrazide. The docking and molecular dynamic have performed to them to study its interaction with Mycobacterium tuberculosis Enoyl-Acyl Carrier Protein Reductase (InhA). Based on this research, all of the compounds were predicted to have a stable interaction with Mycobacterium tuberculosis Enoyl-Acyl Carrier Protein Reductase (InhA) receptor so that they could be used as an anti-tuberculosis drug candidate

Graphical abstract

Section snippets

Rationale

Isoniazid, a hydrazide compound derived from isonicotinic acid compounds (pyridine-4-carbohydrate), is one of the first-line drugs for tuberculosis. Isonicotinylhydrazide (INH) enables KatG to establish nicotinamide adenine dinucleotide (NAD). These additives inhibit the enzyme reduction enzymes InhA and acyl carrier protein (ACP) reductase, resulting in the synthesis of type II fatty acids, which in turn synthesize mycolic acid, which causes cell death [1].

Previous studies have modified

Macromolecule and Ligands Preparation

The X-ray crystal structure of Mycobacterium Tuberculosis Enoyl-Acyl Carrier Protein Reductase was downloaded from the Protein Data Bank (PDB ID: 2 × 23, Resolution: 1.087 Å) [21]. Four structures of isoniazid derivatives, i.e., isonicotinohydrazide (1-isonicotinoylsemicarbazide, 1-isonicotinoylthiosemi carbazide, N'-(1, 3-dimethyl-1H-pyrazole-5-carbonyl)isonicotino hydrazide, dan N'-(1,2,3-thiadiazole-4-carbonyl)isonicotinohydrazide) (Fig. 1) were drawn and optimized with MarvinSketch 5.2.5.1

Data, Value and Validation

In this study, we have designed four isoniazid derivative compounds (Fig. 1). Four isoniazid derivative compounds were drawn and prepared with a Chemaxon program. The proposal of synthetic pathway for these four compounds can be shown in Fig. 2 [37], [38], [39], [40].

The compounds are discharged on the Mycobacterium Tuberculosis Enoyl-Acyl Carrier Protein Reductase (Fig. 3) with the Autodock program. Before being used for docking the Mycobacterium Tuberculosis Enoyl-Acyl Carrier Protein

Conclusions

The current study describes the binding of isoniazid derivatives to Mycobacterium Tuberculosis Enoyl-Acyl Carrier Protein Reductase. Molecular docking shows that compound 4 has the best interaction if it was compared with the other compounds. Analysis on RMSD that all isoniazid derivatives are stable in the InhA active site. Based on in silico study, all of the compounds were predicted to have a stable interaction with Mycobacterium tuberculosis Enoyl-Acyl Carrier Protein Reductase (InhA)

Declaration of Competing Interest

The authors have no conflicts of interest to declare.

Acknowledgments

We would like to thank Universitas Perjuangan Tasikmalaya on the research grant in 2017 and STIKes Bakti Tunas Husada Tasikmalaya for all facilities in the completion of this project. We would like to especially to the Indonesian Ministry of Research, Technology and Higher Education (Ristekdikti) on BSLN grant 2018.

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A series of aliphatic isoniazid carbo(x/thio)amides has been synthesized by a facile one-pot green method in aqueous media by harnessing microwave irradiations. In vitro antitubercular screening of the synthesized compounds against Mycobacterium tuberculosis H37Rv (MTB strain) reveals promising antimycobacterial potential with MIC in the range of 1 to 4 µg/ml. A computational approach comprising DFT modeling, molecular docking and ADMET analysis was executed to elucidate the chemical nature, binding affinity and ADMET efficacy of the lead compounds. The docking of synthesized analogs with InhA displays weak binding interactions with the receptor and the absence of important interactions specific to direct inhibitors. However, the docking results illustrate notable binding affinity of the synthesized molecules with the KatG receptor 1SJ2 and compounds 3h and 3e showed the best docking scores (-7.2 and -6.8 kcal/mol, respectively) indicating the KatG mediated mechanism of InhA inhibition similar to isoniazid. In silico ADMET analysis of the title compounds indicate their outstanding pharmacokinetic proficiency and lower toxicity than isoniazid. The bioavailability radar further illustrates their exemplary oral availability and drug-likeliness.
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Data ArticleDocking and molecular dynamic study of isoniazid derivatives as anti-tuberculosis drug candidate

Abstract

Graphical abstract

Section snippets

Rationale

Macromolecule and Ligands Preparation

Data, Value and Validation

Conclusions

Declaration of Competing Interest

Acknowledgments

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Chem. Biol. Interact.

Bioorg. Med. Chem.

Eur. J. Med. Chem.

J. Biol. Chem.

Drug Discov. Today Technol.

J. Mol. Biol.

Design, synthesis and evaluation of antitubercular activity of amino azetidinones from isoniazid

Int. J. Pharm. Sci. Res.

Synthesis, characterization and antimicrobial studies of novel ligand (Diethyl 5-Amino 4-Methyl

World J.f Pharm. Res.

Synthesis, characterization and in-vitro antitubercular activity of isoniazid-gelatin conjugate: Antitubercular isoniazid-gelatin conjugate

J. Pharm. Pharmacol.

Synthesis and antitubercular activity of heteroaromatic Isonicotinoyl and 7-Chloro- 4-Quinolinyl hydrazone derivatives

The Sci. World J.

Synthesis of various isoniazidothiazolidinones and their imidoxy derivatives of potential biological interest

Arkivoc

A study on antitubercular and antimicrobial activity of isoniazid derivative

Zahedan J. Res. Med. Sci.

N-Substituted 2-Isonicotinoylhydrazinecarboxamides — new Antimycobacterial Active Molecules

Molecules

Synthesis and Characterization of Methyl-2-hydroxy-5-{(1)-1-[2- (pyridin-4-ylcarbonyl) hydrazinylidene]butyl}benzoate, a New Isonicotinoylhydrazone Derivative of Methyl Salicylate,

In vitro and in vivo activities of acylated derivatives of isoniazid against mycobacterium tuberculosis

Drug Des. Discov.

Synthesis, characterization, and antimicrobial studies of novel 1,3,4-thiadiazolium-5-thiolates

Med. Chem. Res.

Design and synthesis of substituted clubbed triazolyl thiazole as XDR & MDR antituberculosis agents

Der Chemica Sinica

The Biology Activities of Isonicotinohydrazide Derivatives as an Anti-tuberculosis Candidate

J. Phys. Conf. Ser.

Synthesis and in vitro anti-tubercular activity of a series of N- (Disubstitutedbenzoyl)Isoniazid Derivatives

Lett. Drug Des. Discov.

Data Article
Docking and molecular dynamic study of isoniazid derivatives as anti-tuberculosis drug candidate