title: Identification of potential leads against 4-hydroxytetrahydrodipicolinate synthase from Mycobacterium tuberculosis.
abstract: 4-hydroxy-tetrahydrodipicolinate synthase (DHDPS) is an important enzyme needed for the biosynthesis of lysine and many more key metabolites in Mycobacterium tuberculosis (Mtb). Inhibition of DHDPS is supposed to a promising therapeutic target due to its specific role in sporulation, cross-linking of the peptidiglycan polymers and biosynthesis of amino acids. In this work, a known inhibitor-based similarity search was carried out against a natural products database (Super Natural II) towards identification of more potent phyto-inhibitors. Molecular interaction studies were accomplished using three different tools to understand and establish the participation of active site residues as the key players in stabilizing the binding mode of ligands and target protein. The best phyto-compound deduced on the basis of binding affinity was further used as a template to make similarity scan across the PubChem Compound database (score > = 80 %) to get more divesred leads. In this search 5098 hits were obtained that further reduced to 262 after drug-likeness filtration. These phytochemicallike compounds were docked at the active site of DHDPS.Then, those hits selected from docking analysis that showing stronger binding and forming maximum H-bonds with the active site residues (Thr54, Thr55, Tyr143, Arg148 and Lys171). Finally, we predicted one phytochemical compound (SN00003544), two PubChem-compounds (CID41032023, CID54025334) akin to phytochemical molecule showing better interactions in comaprison of known inhibitors of target protein.These findings might be further useful to gain the structural insight into the designing of novel leads against DapA family.
authors.affiliation: Department of Biosciences, Faculty of Applied Sciences, Integral University Lucknow, Uttar Pradesh, India-226026.
authors.forename: Ajijur
authors.initials: A
authors.lastname: Rehman
authors.affiliation: Department of Bioengineering, Faculty of Engineering, Integral University Lucknow, Uttar Pradesh, India-226026.
authors.forename: Salman
authors.initials: S
authors.lastname: Akhtar
authors.affiliation: Department of Bioengineering, Faculty of Engineering, Integral University Lucknow, Uttar Pradesh, India-226026.
authors.forename: Mohd Haris
authors.initials: MH
authors.lastname: Siddiqui
authors.affiliation: Department of Bioengineering, Faculty of Engineering, Integral University Lucknow, Uttar Pradesh, India-226026.
authors.forename: Usman
authors.initials: U
authors.lastname: Sayeed
authors.affiliation: Department of Bioengineering, Faculty of Engineering, Integral University Lucknow, Uttar Pradesh, India-226026.
authors.forename: Syed Sayeed
authors.initials: SS
authors.lastname: Ahmad
authors.affiliation: Department of Biosciences, Faculty of Applied Sciences, Integral University Lucknow, Uttar Pradesh, India-226026.
authors.forename: Jamal M
authors.initials: JM
authors.lastname: Arif
authors.affiliation: Department of Bioengineering, Faculty of Engineering, Integral University Lucknow, Uttar Pradesh, India-226026.
authors.forename: M Kalim A
authors.initials: MK
authors.lastname: Khan
keywords: DHDPS; Mycobacterium tuberculosis; docking; drug-likeness; phyto-compound