Title

Identification of potential leads against 4-hydroxytetrahydrodipicolinate synthase from Mycobacterium tuberculosis

Authors

Ajijur Rehman1, Salman Akhtar2, Mohd Haris Siddiqui2, Usman Sayeed2, Syed Sayeed Ahmad2, Jamal M. Arif1, M. Kalim A. Khan2*

Affiliation

1Department of Biosciences, Faculty of Applied Sciences, Integral University Lucknow, Uttar Pradesh, India-226026; 2Department of Bioengineering, Faculty of Engineering, Integral University Lucknow, Uttar Pradesh, India-226026.

Email

M. Kalim A. Khan, Ph.D. - E-mail: mkakhan@iul.ac.in, mkakhaniu@gmail.com Tel: 0522-2890812; Fax: 0522-2890809; Mobile: +91-8853265807; *Corresponding author

Article Type

Hypothesis

Date

Recieved October 21, 2016; Accepted November 19, 2016; Published December 2, 2016

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 phyto-chemical like 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.

Keywords:

DHDPS, Mycobacterium tuberculosis, docking, phyto-compound, drug-likeness.

Citation

Rehman et al. Bioinformation 12(11): 400-407 (2016)

Edited by

P Kangueane

ISSN

0973-2063

Publisher

Biomedical Informatics

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.