Virtual screening of combinatorial library of novel benzenesulfonamides on mycobacterial carbonic anhydrase II

Open access


Combinatorial library of novel benzenesulfonamides was docked (Schrodinger Glide) into mycobacterial carbonic anhydrase (mtCA II) and human (hCA II) isoforms with an aim to find drug candidates with selective activity on mtCA II. The predicted selectivity was calculated based on optimized MM-GBSA free energies for ligand enzyme interactions. Selectivity, LogP (o/w) and interaction energy were used to calculate the selection index which determined the subset of best scoring molecules selected for further evaluation. Structure-activity relationship was found for fragment subsets, showing us the possible way regarding how to influence lipophilicity without affecting ligand-enzyme binding properties.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • [1] Behnke CA Le Trong I Godden JW et al. Atomic resolution studies of carbonic anhydrase II. Acta Crystallogr. 2010;66:616-627.

  • [2] Ceruso M Vullo D Scozzafava A Supuran CT. Inhibition of human carbonic anhydrase isoforms I-XIV with sulfonamides incorporating fluorine and 135-triazine moieties. Bioorg Med Chem. 2013;21:6929-6936.

  • [3] Covarrubias AS Bergfors T Jones TA Hogbom M. Structural mechanics of the pH-dependent activity of beta-carbonic anhydrase from Mycobacterium tuberculosis. J Biol Chem. 2006;281:4993-4999.

  • [4] Covarubias AS Larsson AM Hogbom M et al. Structure and Function of Carbonic Anhydrases from Mycobacterium tuberculosis. J Biol Chem. 2005;280:18782-18789.

  • [5] Friesner RA Murphy RB Repasky MP Frye LL Greenwood JR Halgren TA Sanschagrin PC Mainz DT. Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes. J Med Chem. 2006;49:6177-6196.

  • [6] Keckesova S Sedlarova E Cizmarik J et al. Antimycobacterial activity of novel derivatives of arylcarbonyloxyaminopro-panols. Ceska Slov Farm. 2009;58:203-207.

  • [7] Li J Abel R Zhu K et al. The VSGB 2.0 Model: A Next Generation Energy Model for High Resolution Protein Structure Modelling. Proteins 2011;79:2794-2812.

  • [8] Lipinski C Lombardo F Dominy BW Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46:3-26.

  • [9] Maresca A. Carbonic anhydrase inhibitors. Inhibition of the Rv1284 and Rv3273 beta-carbonic anhydrases from Mycobacterium tuberculosis with. Bioorg Med Chem Lett. 2009;19:4929-4932.

  • [10] Sassetti CM Rubin EJ. Genetic requirements for mycobacterial survival during infection. Proc Natl Acad Sci U S A. 2003;100:12989-12994.

  • [11] Shelley JC Cholleti A Frye L Greenwood JR Timlin MR Uchimaya M. Epik: a software program for pKa prediction and protonation state generation for drug-like molecules. J Comp-Aided Mo. Design. 2007;21:681-691.

  • [12] Showalter HD Denny WA. A roadmap for drug discovery and its translation to small molecule agents in clinical development for tuberculosis treatment. Tuberculosis (Edinb). 2008;88(1 suppl):s3- s17.

  • [13] Supuran CT. Carbonic anhydrases - An overview. Curr Pharm Des. 2008;14:603-614.

  • [14] Supuran CT. Carbonic Anhydrase Inhibition/Activation: Trip of a Scientist Around the World in the Search of Novel Chemotypes and Drug Targets. Curr Pharm Des. 2010;16:3233-3245.

  • [15] Upadhayaya RS Kulkarni GM Vasireddy NR Vandavasi JK Dixit SS Sharma V Chattopadhyaya J. Design synthesis and biological evaluation of novel triazole urea and thiourea derivatives of quinoline against Mycobacterium tuberculosis. Bioorg Med Chem 2009;17:4681-4692.

  • [16] Veber DF Johnson SR Cheng HY Smith BR Ward KW Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45:2615-2623.

  • [17] Waisser K Dolezal R Palat K Cizmarik J Kaustova J. QSAR study of antimycobacterial activity of quaternary ammonium salts of piperidinylethyl esters of alkoxysubstituted phenylcarbamic acids. Folia Microbiologica. 2006;51:21-24.

  • [18] WHO. WHO Global tuberculosis report. WHO; 2013.

Journal information
Impact Factor

CiteScore 2018: 0.39

SCImago Journal Rank (SJR) 2018: 0.128
Source Normalized Impact per Paper (SNIP) 2018: 0.337

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 280 123 1
PDF Downloads 150 75 6