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Thymidylate kinase (TMK) is a pivotal enzyme in Mycobacterium tuberculosis (Mtb), crucial for phosphorylating thymidine monophosphate (dTMP) to thymidine diphosphate (dTDP), thereby playing a critical role in DNA biosynthesis. Dysregulation or inhibition of TMK activity disrupts DNA replication and cell division, making it an attractive target for anti-tuberculosis drug development. In this study, the statistically validated pharmacophore mode was developed from a set of known TMK inhibitors. Further, the robust pharmacophore was considered for screening the Enamine database. The chemical space was reduced through multiple molecular docking approaches, pharmacokinetics, and absolute binding energy estimation. Two different molecular docking algorithms favor the strong binding affinity of the proposed molecules towards TMK. Machine learning-based absolute binding energy also showed the potentiality of the proposed molecules. The binding interactions analysis exposed the strong binding affinity between the proposed molecules and active site amino residues of TMK. Several statistical parameters from all atoms MD simulation explained the stability between proposed molecules and TMK in the dynamic states. The MM-GBSA approach also found a strong binding affinity for each proposed molecule. Therefore, the proposed molecules might be crucial TMK inhibitors for managing Mtb inhibition subjected to in vitro/in vivo validations., (© 2024. The Author(s).)

In this work we investigated the Pks13-TE domain, which plays a critical role in the viability of the mycobacteria. In this report, we have used a series of AI and Physics-based tools to identify Pks13-TE inhibitors. The Reinvent 4, pKCSM, KDeep, and SwissADME are AI-ML-based tools. AutoDock Vina, PLANTS, MDS, and MM-GBSA are physics-based methods. A combination of these methods yields powerful support in the drug discovery cycle. Known inhibitors of Pks13-TE were collected, curated, and used as input for the AI-based tools, and Mol2Mol molecular optimisation methods generated novel inhibitors. These ligands were filtered based on physics-based methods like molecular docking and molecular dynamics using multiple tools for consensus generation. Rigorous analysis was performed on the selected compounds to reduce the chemical space while retaining the most promising compounds. The molecule interactions, stability of the protein-ligand complexes and the comparable binding energies with the native ligand were essential factors for narrowing the ligands set. The filtered ligands from docking, MDS, and binding energy colocations were further tested for their ADMET properties since they are among the essential criteria for this series of molecules. It was found that ligands Mt1 to Mt6 have excellent predicted pharmacokinetic, pharmacodynamic and toxicity profiles and good synthesisability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tuberculosis (TB) is one of the life-threatening infectious diseases with prehistoric origins and occurs in almost all habitable parts of the world. TB mainly affects the lungs, and its etiological agent is Mycobacterium tuberculosis (Mtb). In 2022, more than 10 million people were infected worldwide, and 1.3 million were children. The current study considered the in-silico and machine learning (ML) approaches to explore the potential anti-TB molecules from the SelleckChem database against Enoyl-Acyl Carrier Protein Reductase (InhA). Initially, the entire database of ∼ 119000 molecules was sorted out through drug-likeness. Further, the molecular docking study was conducted to reduce the chemical space. The standard TB drug molecule's binding energy was considered a threshold, and molecules found with lower affinity were removed for further analyses. Finally, the molecules were checked for the pharmacokinetic and toxicity studies, and compounds found to have acceptable pharmacokinetic parameters and were non-toxic were considered as final promising molecules for InhA. The above approach further evaluated five molecules for ML-based toxicity and synthetic accessibility assessment. Not a single molecule was found toxic and each of them was revealed as easy to synthesise. The complex between InhA and proposed and standard molecules was considered for molecular dynamics simulation. Several statistical parameters showed the stability between InhA and the proposed molecule. The high binding affinity was also found for each of the molecules towards InhA using the MM-GBSA approach. Hence, the above approaches and findings exposed the potentiality of the proposed molecules against InhA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tuberculosis is a prominent aliment throughout the world and a leading cause of mortality among infectious diseases. Drug development for multi-drug resistance and reducing the current therapy time is the top priority. Mycobacterial membrane protein large 3 (MmpL3) is a promising target with high potential, however, it has not been explored to its greatest potential. It is a membrane transporter that translocates trehalose-monomycolate which is a precursor for the synthesis of mycolic acid that is essential for the synthesis of the bacterial cell wall and is pathogenic in nature. In this review, we have discussed the current development of MmpL3 inhibitors, different scaffolds, their derivatives, and their synthetic schemes and provide insight into the challenges in developing these inhibitors., (© 2021 Wiley-VCH GmbH.)

Enoyl acyl carrier protein reductase (InhA) is a key enzyme involved in fatty acid synthesis mainly mycolic acid biosynthesis that is a part of NADH dependent acyl carrier protein reductase family. The aim of the present literature is to underline the different scaffolds or enzyme inhibitors that inhibit mycolic acid biosynthesis mainly cell wall synthesis by inhibiting enzyme InhA. Various scaffolds were identified based on the screening technologies like high throughput screening, encoded library technology, fragment-based screening. The compounds studied include indirect inhibitors (Isoniazid, Ethionamide, Prothionamide) and direct inhibitors (Triclosan/Diphenyl ethers, Pyrrolidine Carboxamides, Pyrroles, Acetamides, Thiadiazoles, Triazoles) with better efficacy against drug resistance. Out of the several scaffolds studied, pyrrolidine carboxamides were found to be the best molecules targeting InhA having good bioavailability properties and better MIC. This review provides with a detailed information, analysis, structure activity relationship and useful insight on various scaffolds as InhA inhibitors., (Copyright © 2021. Published by Elsevier Inc.)

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb). In the present age, due to the rapid increase in antibiotic resistance worldwide, TB has become a major threat to human life. Regardless of significant efforts have been inclined to improve the healthcare systems for improving diagnosis, treatment, and anticipatory measures controlling TB is challenging. To date, there are no such therapeutic chemical agents available to fight or control the bacterial drug-resistance. The catalase-peroxidase enzyme (katG) which encoded by the katG gene of Mtb is most frequently getting mutated and hence promotes Isoniazid resistance by diminishing the normal activity of katG enzyme. In the current study, an effort has been intended to find novel and therapeutically active antibacterial chemical compounds through pharmacoinformatics methodologies. Initially, the five mutant katG were generated by making mutation of Ser315 by Thr, Ile, Arg, Asn, and Gly followed by structural optimizations. About eight thousand small molecules were collected from the Asinex antibacterial library. All molecules were docked to active site of five mutant katG and wild type katG. To narrow down the chemical space several criteria were imposed including, screening for highest binding affinity towards katG proteins, compounds satisfying various criterion of drug-likeliness properties like Lipinski's rule of five (RO5), Veber's rule, absorption, distribution, metabolism, and excretion (ADME) profile, and synthetic accessibility. Finally, five molecules were found to be important antibacterial katG inhibitors. All the analyzed parameters suggested that selected molecules are promising in nature. Binding interactions analysis revealed that proposed molecules are efficient enough to form a number of strong binding interactions with katG proteins. Dynamic behavior of the proposed molecules with katG protein was evaluated through 100 ns molecular dynamics (MD) simulation study. Parameters calculated from the MD simulation trajectories adjudged that all molecules can form stable complexes with katG. High binding free energy of all proposed molecules definitely suggested strong affection towards the katG. Hence, it can be concluded that proposed molecules might be used as antibacterial chemical component subjected to experimental validation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1), a vital enzyme for cell wall synthesis, plays a crucial role in the formation of lipoarabinomannan and arabinogalactan. It was first reported as a druggable target on the basis of inhibitors discovered in high throughput screening of a drug library. Since then, inhibitors with different types of chemical scaffolds have been reported for their activity against this enzyme. Formation of a covalent or noncovalent bond by the interacting ligand with the enzyme causes loss of its catalytic activity which ultimately leads to the death of the mycobacterium. This Perspective describes various DprE1 inhibitors as anti-TB agents reported to date.