title: Discovery of novel inhibitors targeting the Mycobacterium tuberculosis O-acetylserine sulfhydrylase (CysK1) using virtual high-throughput screening.
abstract: Cysteine biosynthesis in Mycobacterium tuberculosis (MTB) is crucial for this pathogen to combat oxidative stress and for long term survival in the host. Hence inhibition of this pathway is attractive for developing novel drugs against tuberculosis. In the present study, the crystal structure of the mycobacterial enzyme O-acetylserine sulfhydrylase CysK1 bound to an oligopeptide inhibitor was used as a framework for virtual screening of the BITS-Pilani in-house database to identify new scaffolds as CysK1 inhibitors. Thirty compounds were synthesized and evaluated in vitro for their ability to inhibit CysK1, activity against M. tuberculosis and cytotoxicity as steps towards the derivation of structure-activity relationships (SAR) and lead optimization. Compound 8-nitro-4-(2-(trifluoromethyl)phenyl)-4,4a-dihydro-2H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidine-2,5(3H)-dione (4n) emerged as the most promising lead with an IC(50) of 17.7 μM for purified CysK1 and MIC of 7.6 μM for M. tuberculosis, with little or no cytotoxicity (>50 μM).
authors: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, RR District, Hyderabad 500078, Andhra Pradesh, India.
authors: Variam Ullas
authors: VU
authors: Jean Kumar
authors: Ömer
authors: Ö
authors: Poyraz
authors: Shalini
authors: S
authors: Saxena
authors: Robert
authors: R
authors: Schnell
authors: Perumal
authors: P
authors: Yogeeswari
authors: Gunter
authors: G
authors: Schneider
authors: Dharmarajan
authors: D
authors: Sriram
mesh_terms: D003547:Cysteine Synthase / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D003547:Cysteine Synthase