Mycobacterium tuberculosis sterol 14α-demethylase inhibitor sulfonamides : Identified by high-throughput screening

Department of Chemistry, Inorganic Chemistry Section, Jadavpur University, Kolkata-700 032, India E-mail : c_r_sinha@yahoo.com Fax : 91-33-2414658 Manuscript received 13 January 2017, accepted 07 February 2017 Tuberculosis is a deadly infectious disease caused by Mycobacterium tuberculosis. Sterol 14α-demethylase cytochrome P450 51(CYP51) is a key target for antibiotic therapy. Azoles are used to disturb functional activity of CYP51 and thus promising antifungal agents. Sulfonamides, anti-microbial drug, also act as antifungal candidate. In this work high-throughput screening approach is used to find sulfonamides for lead candidate as CYP51 inhibitor. A library of 402 sulfonamides from various databases against M. tuberculosis CYP51 (CYP51Mt) are screened and has been examined the top binding hits for their inhibitory effects. Docking results show that binding affinity of newly searched ligands is higher than known tuberculosis drugs. Lipinski’s rule of five protocols is followed to screen drug likeness and ADMET filtration is also used to value toxicity. DFT computation of optimized geometry and molecular orbitals have been used to correlate with the drug likeness. Pharmacophore generation is reported to recognize the binding patterns of inhibitors in the receptor active site. (2R)-2-(2,1,3-Benzothiadiazol-4-ylsulfonylamino)-N-[(1S,2R)-2-methylcyclohexyl]-2- phenylacetamide shows best theoretical efficiency. The compounds also bind to Adenine-Thymine region of tuberculosis Deoxyribonucleic acid (DNA). To observe the stability and flexibility of inhibitors the molecular dynamics simulation (MD) has been carried out