Piggyback drug development: (Molecular docking of Entacapone analogues as direct M. tuberculosis InhA inhibitors) (original) (raw)
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International Journal of Molecular Sciences, 2022
Tuberculosis (TB) caused by Mycobacterium tuberculosis is still a serious public health concern around the world. More treatment strategies or more specific molecular targets have been sought by researchers. One of the most important targets is M. tuberculosis’ enoyl-acyl carrier protein reductase InhA which is considered a promising, well-studied target for anti-tuberculosis medication development. Our team has made it a goal to find new lead structures that could be useful in the creation of new antitubercular drugs. In this study, a new class of 1,2,3- and 1,2,4-triazole hybrid compounds was prepared. Click synthesis was used to afford 1,2,3-triazoles scaffold linked to 1,2,4-triazole by fixable mercaptomethylene linker. The new prepared compounds have been characterized by different spectroscopic tools. The designed compounds were tested in vitro against the InhA enzyme. At 10 nM, the inhibitors 5b, 5c, 7c, 7d, 7e, and 7f successfully and totally (100%) inhibited the InhA enzyme. The IC50 values were calculated using different concentrations. With IC50 values of 0.074 and 0.13 nM, 7c and 7e were the most promising InhA inhibitors. Furthermore, a molecular docking investigation was carried out to support antitubercular activity as well as to analyze the binding manner of the screened compounds with the target InhA enzyme’s binding site.
Tuberculosis, a disease largely observed to be caused by Mycobacterium tuberculosis bacteria, affects mainly to the lung. Most of anti-tubercular drug therapy leads to development of multi-drug resistant tuberculosis (MDR-TB) or extensive-drug resistant tuberculosis (XDR-TB) caused by extensive usage of anti-TB drugs. COMT inhibitor which are used in treatment of Parkinson's disease have some similarity to the enoyl acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis, which is responsible for synthesis of mycolic acid, essential component of bacterial cell wall. Molecular docking study of COMT inhibitor was performed on enoyl acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis having PDB ID 1ENY by using Biomed CAche software. Docking study performed on 150 molecules of COMT inhibitor out of them twelve best poses [)] are selected and evaluated for Biological activity by using PASS Online and Toxicity study performed by using OSIRIS property explorer. C48 having a good binding affinity to InhA and shows better anti-tubercular activity (Pa-0.419, Pi-0.0026) and have no major toxicity found by OSIRIS property explorer.
Biointerface Research in Applied Chemistry, 2021
The enoyl-acyl carrier protein (ACP) reductase (InhA) of Mycobacterium tuberculosis elongates acyl fatty acids, which are progenitors of mycolic acids and that are mycobacterial cell wall parts. The aim is to discover potent therapeutic novel bioactive compounds as enoyl-acyl carrier protein (ACP) reductase (InhA, PDB ID: 4U0J) antagonists using an in silico drug design scheme. Structure-based computerized prediction of drug-receptor interactions. PyRx virtual screening tool was used to conduct molecular docking investigations on enoyl-ACP reductase. A target-based ligand selection strategy to choose ligand compounds was employed. The ligand structure was chosen using LEA3D-CNRS. Medication data set that was approved by the FDA: 2028 molecule (s) were used in the study. Around 27 bioactive molecules can bind to the 4U0J, with docking scores ranging from -6.2 to -11.2 Kcal/mol. Compound CHEMBL441373 was shown to have the highest acceptable docking energy (-11.1Kcal/mol), making it a ...
Molecular Docking of Quinolone against INHA to Treat Tuberculosis
International Journal for Research in Applied Science and Engineering Technology IJRASET, 2020
Background: Tuberculosis (TB) is one of the most infectious diseases in the present scenario that is caused when Mycobacterium tuberculosis is found in the body. As tuberculosis is a communicable disease or transferrable disease, it is easily transmitted to another person who remains in contact with the infected person through the inhalation process of air droplets carrying that particular bacteria. The in silico study was carried out to inhibit the activity of INHA by drug molecule with the help of molecular docking to treat tuberculosis. Methods: All studies were based on molecular docking. Docking was carried out between all the ligands and target protein INHA (PDB ID: 5VRL) with the help of docking software. We selected some natural compounds as ligand like Thiophenes, Sulfonamides, Chalcone, Nitroimidazole, Benzimidazole, Lidamycin and Quinolone and INHA (PDB ID: 5VRL) as a target protein. After the protein preparation by Biovia Discovery Studio Visualizer we imported all the ligand in PyRx software for virtual screening. According to the PyRx result and Lipinski’s Rule of Five, Quinolone was the best compound against INHA with its minimum binding energy
Mycobacterium tuberculosis InhA (MtInhA) is an attractive enzyme to drug discovery efforts due to its validation as an effective biological target for tuberculosis therapy. In this work, two different virtual-ligand-screening approaches were applied in order to identify new InhA inhibitors' candidates from a library of ligands selected from the ZINC database. First, a 3-D pharmacophore model was built based on 36 available MtInhA crystal structures. By combining structure-based and ligand-based information, four pharmacophoric points were designed to select molecules able to satisfy the binding features of MtInhA substrate-binding cavity. The second approach consisted of using four well established docking programs, with different search algorithms, to compare the binding mode and score of the selected molecules from the aforementioned library. After detailed analyses of the results, six ligands were selected for in vitro analysis. Three of these molecules presented a satisfactory inhibitory activity with IC 50 values ranging from 24 (±2) μM to 83 (±5) μM. The best compound presented an uncompetitive inhibition mode to NADH and 2-trans-dodecenoyl-CoA substrates, with K i values of 24 (±3) μM and 20 (±2) μM, respectively. These molecules were not yet described as antituberculars or as InhA inhibitors, making its novelty interesting to start efforts on ligand optimization in order to identify new effective drugs against tuberculosis having InhA as a target. More studies are underway to dissect the discovered uncompetitive inhibitor interactions with MtInhA.
Annals of Plant Sciences, 2016
Evolution and the rapid spread of the multidrug resistant Mycobacterium tuberculosis (Mtb) have posed a serious crisis. Moreover, the available first line drugs also confer adverse effects on the patients suffering from tuberculosis (TB) thus making the cure increasingly difficult. Thus the search of novel and potent natural compounds targeting anti-tubercular agents has become inevitable. Here, we report identification of potential natural anti-tubercular candidates targeting Mtb 2-Trans Enoyl Acyl Carrier Protein Reductase (InhA) of the fatty acid pathway using structure based drug designing. In the present study, we selected a total of 154 compounds from three plants i.e. Ginkgo biloba, Neem (Azadirachta indica) and Tea (Camellia sinensis) which were obtained from PubChem Compounds. These compounds were subjected to Lipinski’s rule of five and drug likeness filters. Finally, the compounds were docked at the active site of Mtb InhA (PDB code: 3FNE) using AutoDock Vina to select in...
Journal of Molecular Graphics and Modelling, 2019
2-trans enoyl-acyl carrier protein reductase (InhA) has been identified as a promising target for the development of novel chemotherapy for tuberculosis. In the present study, a series of heteroaryl benzamide derivatives were selected as potent inhibitors against InhA, and their binding properties with InhA were investigated at atomic and electronic levels by ab initio molecular simulations based on protein-ligand docking, classical molecular mechanics optimizations and ab initio fragment molecular orbital (FMO) calculations. The results evaluated by FMO highlight some key interactions between InhA and the derivatives, indicating that the most potent derivative has strong hydrogen bonds with the Met98 side chain of InhA and strong electrostatic interactions with the nicotinamide adenine dinucleotide cofactor. These findings provide informative structural concepts for designing novel heteroaryl benzamide derivatives with higher binding affinity to InhA.
Indian journal of biochemistry & biophysics, 2012
Isoniazid resistance is a serious threat in the battle against the treatment of multi-drug resistant tuberculosis (MDR-TB) and extremely drug-resistant tuberculosis (XDR-TB). Isoniazid is an inhibitor of enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis, which is an important and functional enzyme of the type II fatty acid synthesis system and important therapeutic target. Natural alkaloid tryptanthrin and its analogues have shown anti-tubercular activity against MDR-TB, but their cellular target is unknown. In this work, in silico molecular docking was performed using docking server in order to see the interaction of tryptanthrin and its 15 analogues with InhA of M. tuberculosis. Results showed that among tryptanthrin and its 15 analogues, tryptanthrin and its two analogues exhibited good affinity to the binding site of InhA with free binding energy of -7.94 kcal/mol and inhibition constant (Ki) of 1.50 microm. Active site residues of InhA interacting with t...