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Toward antituberculosis drugs: in silico screening of synthetic compounds against Mycobacterium tuberculosis L,D-transpeptidase 2

Authors Billones J, Carrillo MC, Organo V, Macalino SJ, Sy JB, Emnacen I, Clavio NA, Concepcion G

Received 24 September 2015

Accepted for publication 31 December 2015

Published 11 March 2016 Volume 2016:10 Pages 1147—1157

DOI https://doi.org/10.2147/DDDT.S97043

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Ohad Ilovich

Peer reviewer comments 2

Editor who approved publication: Professor Wei Duan

Junie B Billones,1,2 Maria Constancia O Carrillo,1 Voltaire G Organo,1 Stephani Joy Y Macalino,1 Jamie Bernadette A Sy,1 Inno A Emnacen,1 Nina Abigail B Clavio,1 Gisela P Concepcion3

1Office of the Vice President for Academic Affairs – Emerging Interdisciplinary Research Program: “Computer-aided Discovery of Compounds for the treatment of Tuberculosis in the Philippines,” Department of Physical Sciences and Mathematics, College of Arts and Sciences, 2Institute of Pharmaceutical Sciences, National Institutes of Health, University of the Philippines Manila, Manila, 3Marine Science Institute, University of the Philippines Diliman, Diliman, Quezon City, Philippines

Abstract: Mycobacterium tuberculosis (Mtb) the main causative agent of tuberculosis, is the main reason why this disease continues to be a global public health threat. It is therefore imperative to find a novel antitubercular drug target that is unique to the structural machinery or is essential to the growth and survival of the bacterium. One such target is the enzyme L,D-transpeptidase 2, also known as LdtMt2, a protein primarily responsible for the catalysis of 3→3 cross-linkages that make up the mycolyl–arabinogalactan–peptidoglycan complex of Mtb. In this study, structure-based pharmacophore screening, molecular docking, and in silico toxicity evaluations were employed in screening compounds from a database of synthetic compounds. Out of the 4.5 million database compounds, 18 structures were identified as high-scoring, high-binding hits with very satisfactory absorption, distribution, metabolism, excretion, and toxicity properties. Two out of the 18 compounds were further subjected to in vitro bioactivity assays, with one exhibiting a good inhibitory activity against the Mtb H37Ra strain.

Keywords: antituberculosis drug discovery, virtual screening, docking

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