title: Pharmacoinformatics analysis to identify inhibitors of Mtb-ASADH.
abstract: Aspartate-semialdehyde dehydrogenase (ASADH; EC 1.2.1.11) is a key enzyme in the biosynthesis of essential amino acids in prokaryotes and fungi, inhibition of ASADH leads to the development of novel antitubercular agents. In the present work, a combined structure and ligand-based pharmacophore modeling, molecular docking, and molecular dynamics (MD) approaches were employed to identify potent inhibitors of mycobacterium tuberculosis (Mtb)-ASADH. The structure-based pharmacophore hypothesis consists of three hydrogen bond acceptor (HBA), two negatively ionizable, and one positively ionizable center, while ligand-based pharmacophore consists of additional one HBA and one hydrogen bond donor features. The validated pharmacophore models were used to screen the chemical databases (ZINC and NCI). The screened hits were subjected to ADME and toxicity filters, and subsequently to the molecular docking analysis. Best-docked 25 compounds carry the characteristics of highly electronegative functional groups (-COOH and -NO2) on both sides and exhibited the H-bonding interactions with highly conserved residues Arg99, Arg249, and His256. For further validation of docking results, MD simulation studies were carried out on two representative compounds NSC51108 and ZINC04203124. Both the compounds remain bound to the key active residues of Mtb-ASADH during the MD simulations. These identified hits can be further used for lead optimization and in the design more potent inhibitors against Mtb-ASADH.
authors.affiliation: a Department of Pharmacoinformatics , National Institute of Pharmaceutical Education and Research (NIPER) , Sector-67, S. A. S. Nagar 160 062 , Punjab , India.
authors.forename: Rajender
authors.initials: R
authors.lastname: Kumar
authors.affiliation: a Department of Pharmacoinformatics , National Institute of Pharmaceutical Education and Research (NIPER) , Sector-67, S. A. S. Nagar 160 062 , Punjab , India.
authors.forename: Prabha
authors.initials: P
authors.lastname: Garg
authors.affiliation: a Department of Pharmacoinformatics , National Institute of Pharmaceutical Education and Research (NIPER) , Sector-67, S. A. S. Nagar 160 062 , Punjab , India.|b Department of Medicinal Chemistry , National Institute of Pharmaceutical Education and Research (NIPER) , Sector-67, S. A. S. Nagar 160 062 , Punjab , India.
authors.forename: P V
authors.initials: PV
authors.lastname: Bharatam
mesh_terms: D000601:Amino Acids, Essential / Q000096:biosynthesis / Q000737:chemistry*; D001223:Aspartate-Semialdehyde Dehydrogenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D011387:Prokaryotic Cells / Q000201:enzymology; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000601:Amino Acids, Essential; D004791:Enzyme Inhibitors; D008024:Ligands; D001223:Aspartate-Semialdehyde Dehydrogenase
keywords: Mtb-ASADH; inhibitor design; molecular docking and molecular dynamics; pharmacophore modeling