title: In-silico Metabolome Target Analysis Towards PanC-based Antimycobacterial Agent Discovery.
abstract: Mycobacterium tuberculosis, the main cause of tuberculosis (TB), has still remained a global health crisis especially in developing countries. Tuberculosis treatment is a laborious and lengthy process with high risk of noncompliance, cytotoxicity adverse events and drug resistance in patient. Recently, there has been an alarming rise of drug resistant in TB. In this regard, it is an unmet need to develop novel antitubercular medicines that target new or more effective biochemical pathways to prevent drug resistant Mycobacterium. Integrated study of metabolic pathways through in-silico approach played a key role in antimycobacterial design process in this study. Our results suggest that pantothenate synthetase (PanC), anthranilate phosphoribosyl transferase (TrpD) and 3-isopropylmalate dehydratase (LeuD) might be appropriate drug targets. In the next step, in-silico ligand analysis was used for more detailed study of chemical tractability of targets. This was helpful to identify pantothenate synthetase (PanC, Rv3602c) as the best target for antimycobacterial design procedure. Virtual library screening on the best ligand of PanC was then performed for inhibitory ligand design. At the end, five chemical intermediates showed significant inhibition of Mycobacterium bovis with good selectivity indices (SI) ≥10 according to Tuberculosis Antimicrobial Acquisition & Coordinating Facility of US criteria for antimycobacterial screening programs.
authors.affiliation: Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
authors.forename: Baharak
authors.initials: B
authors.lastname: Khoshkholgh-Sima
authors.affiliation: Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran Tehran, Iran.
authors.forename: Soroush
authors.initials: S
authors.lastname: Sardari
authors.affiliation: Department of Pharmacology, Tehran Medical Science Branch, Islamic Azad University, Tehran, Iran.
authors.forename: Jalal
authors.initials: J
authors.lastname: Izadi Mobarakeh
authors.affiliation: Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
authors.forename: Ramezan Ali
authors.initials: RA
authors.lastname: Khavari-Nejad
keywords: Antimycobacterial agents; Metabolic pathway; Mycobacterium; Pantothenate synthetase (PanC)