DFT-Based QSAR Modelling of Inhibitory Activity of Coumarins and Sulfocoumarins on Carbonic Anhydrase (CA) Isoforms (CA I and CA II)

Author(s): Erol Eroglu*.

Journal Name: Current Computer-Aided Drug Design

Volume 15 , Issue 3 , 2019

Submit Manuscript
Submit Proposal

Graphical Abstract:


Objective: We present three robust, validated and statistically significant quantitative structure-activity relationship (QSAR) models, which deal with the calculated molecular descriptors and experimental inhibition constant (Ki) of 42 coumarin and sulfocoumarin derivatives measured against CA I and II isoforms.

Methods: The compounds were subjected to DFT calculations in order to obtain quantum chemical molecular descriptors. Multiple linear regression algorithms were applied to construct QSAR models. Separation of the compounds into training and test sets was accomplished using Kennard-Stone algorithm. Leverage approach was applied to determine Applicability Domain (AD) of the obtained models.

Results: Three models were developed. The first model, CAI_model1 comprises 30/11 training/test compounds with the statistical parameters of R2=0.85, Q2=0.77, F=27.57, R2 (test) =0.72. The second one, CAII_model2 comprises 30/12 training/test compounds with the statistical parameters of R2=0.86, Q2=0.78, F=30.27, R2 (test) =0.85. The final model, ΔpKi_model3 consists of 25/3 training/ test compounds with the statistical parameters of R2=0.78, Q2=0.62, F=13.80 and R2(test) =0.99.

Conclusion: Interpretation of reactivity-related descriptors such as HOMO-1 and LUMO energies and visual inspection of their maps of orbital electron density leads to a conclusion that the binding free energy of the entire binding process may be modulated by the kinetics of the hydrolyzing step of coumarins.

Keywords: QSAR, Coumarins, Carbonic anhydrase, isozyme selectivity, frontier orbitals, Multiple Linear Regression (MLR), DFT, drug design.

Supuran, C.T. Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators. Nat. Rev. Drug Discov., 2008, 7, 168-181.
Scozzafava, A.; Mastrolorenzo, A.; Supuran, C.T. Carbonic anhydrase inhibitors and activators and their use in therapy. Expert Opin. Ther. Pat., 2006, 16, 1627-1664.
Supuran, C.T.; Scozzafava, A.; Casini, A. Carbonic anhydrase inhibitors. Med. Res. Rev., 2003, 23, 146-189.
Supuran, C.T. In: Drug design of zinc-enzyme inhibitors: Functional, structural, and disease applications,, Eds. Claudiu T. Supuran and Jean-Yves Winum, John Wiley & Sons, Inc., Hoboken, New Jersey,. 2009, 14-38.
Gao, B.B.; Clermont, A.; Rook, S.; Fonda, S.J.; Srinivasan, V.J.; Wojtkowski, M.; Fujimoto, J.G.; Avery, R.L.; Arrigg, P.G.; Bursell, S.E.; Aiello, L.P.; Feener, E.P. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat. Med., 2007, 13, 181-188.
Mincione, F.; Scozzafava, A.; Supuran, C.T. The development of topically acting carbonic anhydrase inhibitors as antiglaucoma agents. Curr. Pharm. Des., 2008, 14, 649-654.
Supuran, C.T. Diuretics: From classical carbonic anhydrase inhibitors to novel applications of the sulfonamides. Curr. Pharm. Des., 2008, 14, 641-648.
Hen, N.; Bialer, M.; Yagen, B.; Maresca, A.; Aggarwal, M.; Robbins, A.H.; Supuran, C.T. Anticonvulsant 4-aminobenzenesulfonamide derivatives with branched-alkylamide moieties: X-ray crystallography and inhibition studies of human carbonic anhydrase isoforms I, II, VII, and XIV. J. Med. Chem., 2011, 54, 3977-3981.
De Simone, G.; Scozzafava, A.; Supuran, C.T. Which carbonic anhydrases are targeted by the antiepileptic sulfonamides and sulfamates? Chem. Biol. Drug Des., 2009, 74, 317-321.
Basnyat, B.; Gertsch, J.H.; Johnson, E.W.; Castro-Marin, F.; Inoue, Y.; Yeh, C. Efficacy of low-dose acetazolamide (125 mg BID) for the prophylaxis of acute mountain sickness: A prospective, double-blind, randomized, placebo-controlled trial. High Alt. Med. Biol., 2003, 4, 45-52.
Swenson, E.R.; Teppema, L.J. Prevention of acute mountain sickness by acetazolamide: As yet an unfinished story. J. Appl. Physiol., 2007, 102, 1305-1307.
Sugrue, M.F. Pharmacological and ocular hypotensive properties of topical carbonic anhydrase inhibitors. Prog. Retin. Eye Res., 2000, 19, 87-112.
Alterio, V.; Di Fiore, A.; D’Ambrosio, K.; Supuran, C.T.; De Simone, G. Multiple binding modes of inhibitors to carbonic anhydrases: How to design specific drugs targeting 15 different isoforms? Chem. Rev., 2012, 112, 4421-4468.
Vu, H.; Pham, N.B.; Quinn, R.J. Direct screening of natural product extracts using mass spectrometry. J. Biomol. Screen., 2008, 13, 265-275.
Maresca, A.; Temperini, C.; Vu, H.; Pham, N.B.; Poulsen, S.A.; Scozzafava, A.; Supuran, C.T. Non-zinc mediated inhibition of carbonic anhydrases: Coumarins are a new class of suicide inhibitors. J. Am. Chem. Soc., 2009, 131, 3057-3062.
Maresca, A.; Temperini, C.; Pochet, L.; Masereel, B.; Scozzafava, A.; Supuran, C.T. Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins. J. Med. Chem., 2009, 53, 335-344.
Maresca, A.; Supuran, C.T. Coumarins incorporating hydroxy-and chloro-moieties selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II. Bioorg. Med. Chem. Lett., 2010, 20, 4511-4514.
Tars, K.; Vullo, D.; Kazaks, A.; Leitans, J.; Lends, A.; Grandane, A.; Supuran, C.T. Sulfocoumarins (1, 2-benzoxathiine-2, 2-dioxides): A class of potent and isoform-selective inhibitors of tumor-associated carbonic anhydrases. J. Med. Chem., 2013, 56, 293-300.
Maresca, A.; Scozzafava, A.; Supuran, C.T. 7, 8-Disubstituted-but not 6,7-disubstituted coumarins selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II in the low nanomolar/subnanomolar range. Bioorg. Med. Chem. Lett., 2010, 20, 7255-7258.
Wagner, J.; Avvaru, B.S.; Robbins, A.H.; Scozzafava, A.; Supuran, C.T.; McKenna, R. Coumarinyl-substituted sulfonamides strongly inhibit several human carbonic anhydrase isoforms: Solution and crystallographic investigations. Bioorg. Med. Chem., 2010, 18, 4873-4878.
Tanc, M.; Carta, F.; Bozdag, M.; Scozzafava, A.; Supuran, C.T. 7-Substituted-sulfocoumarins are isoform-selective, potent carbonic anhydrase II inhibitors. Bioorg. Med. Chem., 2013, 21, 4502-4510.
Gaussian 03; Revision C.02; Frisch, M. J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Montgomery, Jr. J.A.; Vreven, T.; Kudin, K.N.; Burant, J.C.; Millam, J.M.; Iyengar, S.S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G.A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li.; X.; Knox, J.E.; Hratchian, H.P.; Cross, J.B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.E.; Yazyev, O.; Austin, A.J.; Cammi, R.; Pomelli, C.; Ochterski, J.W.; Ayala, P.Y.; Morokuma, K.; Voth, G.A.; Salvador, P.; Dannenberg, J.J.; Zakrzewski, V.G.; Dapprich, S.; Daniels, A.D.; Strain, M.C.; Farkas, O.;Malick, D.K.; Rabuck, A.D.; Raghavachari, K.; Foresman, J.B.; Ortiz, J.V.; Cui, Q.; Baboul, A.G.; Clifford, S.; Cioslowski, J.; Stefanov, B.B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R.L.; Fox, D.J.; Keith, T.; Al-Laham, M.A.; Peng, C.Y.; Nanayakkara, A.; Challacombe, M.; Gill, P.M.W; Johnson, B; Chen, W; Wong, M. W; Gonzalez, C; and Pople, J. A; Gaussian; Inc.; Wallingford CT; 2004.
Parr, R.G.; Yang, W. Density functional theory of atoms and molecules; Oxford University Press: New York, 1989.
Becke, A.D. Density‐functional thermochemistry. I. The effect of the exchange‐only gradient correction. J. Chem. Phys., 1992, 96, 2155-2160.
CODESSATM III, 12456 W, 62nd Terrace, Suite D, Shawnee, KS 66216, USA.
CODESSA, References Manual, V. 2.13 (PC). Semichem, 7204, Mullen, Shawnee, KS, USA, Copyright© Semichem and the University of Florida, 2002.
Kennard, R.W.; Stone, L.A. Computer aided design of experiments. Technometrics, 1969, 11, 137-148.
Puzyn, T.; Mostrag-Szlichtyng, A.; Gajewicz, A.; Skrzyński, M.; Worth, A.P. Investigating the influence of data splitting on the predictive ability of QSAR/QSPR models. Struct. Chem., 2011, 22, 795-804.
Roy, K.; Kar, S.; Das, R.N. Statistical methods in QSAR/QSPR. In:A primer on QSAR/QSPR modeling; Springer International Publishing, 2015, pp. 37-59.
Atkinson, A.C. Plots, transformations and regression; Clarendon Press: Oxford, 1985.
Sahigara, F.; Mansouri, K.; Ballabio, D.; Mauri, A.; Consonni, V.; Todeschini, R. Comparison of different approaches to define the applicability domain of QSAR models. Molecules, 2012, 17, 4791-4810.
Murray, J.S.; Politzer, P. The electrostatic potential: An overview. WIRES Comput. Mol. Sci., 2011, 1, 153-163.
Politzer, P.; Murray, J.S.; Peralta‐Inga, Z. Molecular surface electrostatic potentials in relation to noncovalent interactions in biological systems. Int. J. Quantum Chem., 2001, 85, 676-684.
Murray, J.S.; Lane, P.; Brinck, T.; Politzer, P. Relationships between computed molecular properties and solute-solvent interactions in supercritical solutions. J. Phys. Chem., 1993, 97, 5144-5148.
Yorulmaz, N.; Oltulu, O.; Eroğlu, E. Development of selective QSAR models and molecular docking study for inhibitory activity of sulfonamide derivatives against carbonic anhydrase isoforms II and IX. J. Mol. Struct., 2018, 1163, 270-279.
Tsuneda, T.; Singh, R.K.; Chattaraj, P.K. Diagrams for comprehensive molecular orbital-based chemical reaction analyses: Reactive orbital energy diagrams. Phys. Chem. Chem. Phys., 2018, 20, 14211-14222.
Reenu, V. Role of exchange and correlation in the real external prediction of mutagenicity: Performance of hybrid and meta-hybrid exchange-correlation functionals. RSC Advances, 2015, 5, 29238-29251.
Vijayaraj, R.; Subramanian, V.; Chattaraj, P.K. Comparison of global reactivity descriptors calculated using various density functionals: A QSAR perspective. J. Chem. Theory Comput., 2009, 5, 2744-2753.
Fayet, G.; Jacquemin, D.; Wathelet, V.; Perpete, E.A.; Rotureau, P.; Adamo, C. Excited-state properties from ground-state DFT descriptors: A QSPR approach for dyes. J. Mol. Graph. Model., 2010, 28, 465-471.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [243 - 251]
Pages: 9
DOI: 10.2174/1573409915666181211112828
Price: $58

Article Metrics

PDF: 19