New InhA Inhibitors Based on Expanded Triclosan and Di-Triclosan Analogues to Develop a New Treatment for Tuberculosis (original) (raw)
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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.
Advances and challenges in drug design against tuberculosis: application of in silico approaches
Expert Opinion on Drug Discovery, 2018
Introduction: Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains the deadliest infectious disease in the world with one-third of the world's population thought to be infected. Over the years, TB mortality rate has been largely reduced; however, this progress has been threatened by the increasing appearance of multidrug-resistant Mtb. Considerable recent efforts have been undertaken to develop new generation antituberculosis drugs. Many of these attempts have relied on in silico approaches, which have emerged recently as powerful tools complementary to biochemical attempts. Areas covered: The authors review the status of pharmaceutical drug development against TB with a special emphasis on computational work. They focus on those studies that have been validated by in vitro and/or in vivo experiments, and thus, that can be considered as successful. The major goals of this review are to present target protein systems, to highlight how in silico efforts compliment experiments, and to aid future drug design endeavors. Expert opinion: Despite having access to all of the gene and protein sequences of Mtb, the search for new optimal treatments against this deadly pathogen are still ongoing. Together with the geometric growth of protein structural and sequence databases, computational methods have become a powerful technique accelerating the successful identification of new ligands.
Scientific Reports, 2015
It is an urgent need to develop new drugs for Mycobacterium tuberculosis (Mtb), and the enzyme, dihydrofolate reductase (DHFR) is a recognised drug target. The crystal structures of methotrexate binding to mt-and h-DHFR separately indicate that the glycerol (GOL) binding site is likely to be critical for the function of mt-DHFR selective inhibitors. We have used in silico methods to screen NCI small molecule database and a group of related compounds were obtained that inhibit mt-DHFR activity and showed bactericidal effects against a test Mtb strain. The binding poses were then analysed and the influence of GOL binding site was studied by using molecular modelling. By comparing the chemical structures, 4 compounds that might be able to occupy the GOL binding site were identified. However, these compounds contain large hydrophobic side chains. As the GOL binding site is more hydrophilic, molecular modelling indicated that these compounds were failed to occupy the GOL site. The most potent inhibitor (compound 6) demonstrated limited selectivity for mt-DHFR, but did contain a novel central core (7H-pyrrolo[3,2-f]quinazoline-1,3-diamine), which may significantly expand the chemical space of novel mt-DHFR inhibitors. Collectively, these observations will inform future medicinal chemistry efforts to improve the selectivity of compounds against mt-DHFR. Tuberculosis (TB) is a deadly infectious disease caused by Mycobacterium tuberculosis (Mtb) that is particularly prevalent in SouthEast Asia and Africa. In 2013, it is estimated that 9 million people developed TB and 1.5 million died from the disease 1. Despite the fact that death from TB is often preventable, the rapid increase of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has resulted in an urgent need to develop new drug targets for Mtb 2,3 .
2021
Tuberculosis is a major global health problem and is still among the top 10 causes of death. The increasing rate of drug resistance to infectious agents has provoked an urgent need to discover novel anti-tuberculosis agents with novel modes of action. In this study, small molecule inhibitors of the proteins encoded by the drug resistant genes, i.e., katG, gyrA, pncA and rpoB of Mycobacterium tuberculosis (M. tuberculosis), were identified using computational methods. In the ligand base pharmacophore, an already reported four ligands for the four proteins encoded by the resistant genes of M. tuberculosis were selected for the generation of pharmacophores. The validated pharmacophores model of all the four proteins, generated on the basis of ligand base, were selected for further screening of ZINC drug like database. As screening results 486 structurally diverse hits for katG, 542 for PncA, 112 for rpoB and 365 for gyrA were mapped and filtered via Lipinski’s rule of five. Finally, on...
Journal of Chemical Information and Modeling, 2019
The enoyl-acyl carrier protein reductase InhA of M. tuberculosis is an attractive, validated target for anti-tuberculosis drug development. Moreover, direct inhibitors of InhA remain effective against InhA variants with mutations associated with isoniazid resistance, offering the potential for activity against MDR isolates. Here, structure based virtual screening supported by biological assays was applied to identify novel InhA inhibitors as potential antituberculosis agents. High-speed Glide SP docking was initially performed against two conformations of InhA differing in the orientation of the active site Tyr158. The resulting hits were filtered for drug-likeness based on Lipinski's rule and avoidance of PAINS-like properties, and finally subjected to Glide XP docking to improve accuracy. Sixteen compounds were identified and selected for in vitro biological assays, of which two (compounds 1 and 7) showed MIC of 12.5 and 25 µg/ml against M. tuberculosis H37Rv, respectively. Inhibition assays against purified recombinant InhA determined IC50 values for these compounds of 0.38 and 0.22 µM, respectively. A crystal structure of the most potent compound, compound 7, bound to InhA revealed the inhibitor to occupy a hydrophobic pocket implicated in binding the aliphatic portions of InhA substrates but distant from the NADH cofactor, i.e. in a site distinct from those occupied by the great majority of known InhA inhibitors. This compound provides an attractive starting template for ligand optimization aimed at discovery of new and effective compounds against M. tuberculosis that act by targeting InhA.
International Journal of Molecular Sciences, 2021
Developing new, more effective antibiotics against resistant Mycobacterium tuberculosis that inhibit its essential proteins is an appealing strategy for combating the global tuberculosis (TB) epidemic. Finding a compound that can target a particular cavity in a protein and interrupt its enzymatic activity is the crucial objective of drug design and discovery. Such a compound is then subjected to different tests, including clinical trials, to study its effectiveness against the pathogen in the host. In recent times, new techniques, which involve computational and analytical methods, enhanced the chances of drug development, as opposed to traditional drug design methods, which are laborious and time-consuming. The computational techniques in drug design have been improved with a new generation of software used to develop and optimize active compounds that can be used in future chemotherapeutic development to combat global tuberculosis resistance. This review provides an overview of th...
Indian Journal of Pharmaceutical Education and Research
Aim and Background: Mycobacterium tuberculosis (TB) remains the leading cause of human death posing one of the most serious threats to public health around the world. New strategies need to be developed to combat the growing danger by multidrug resistance. The present study aims to screen three different compounds inhibiting the binding pocket of Regulatory Repressor Protein EthR of Mycobacterium tuberculosis. In this study we performed pharmacophore modeling based virtual screening to identify the potential inhibitors against EthR of Mycobacterium tuberculosis. Based on the binding energy and hydrogen bond interactions three compounds were selected as potential inhibitors. Materials and Methods: Structure of EthR protein (PDB ID: 5NZ0) was retrieved from pdb databank. Further, we retrieved ligands from ZINC database (ZINC223412753, ZINC030691754, ZINC170602403). Next, Computational screening, Docking studies and Molecular dynamic simulations were performed to validate the stability of the complexes. Results: The molecular docking showed that all ligands interact with EthR protein of Mycobacteriam. Further, molecular dynamics simulation showed that ligand ZINC223412753 form comparatively more stable complex with EthR. Results showed that all the three ligands could be a potential inhibitor of EthR. Conclusion: These compounds can serve as a starting point in rational design of selective potent inhibitors against Mycobacterium tuberculosis.