The Utility of Calculated Proton Affinities in Drug Design: A DFT Study
Daniel Moscoh Ayine-Tora A and Jóhannes Reynisson A B
+ Author Affiliations
- Author Affiliations
A School of Chemical Sciences, University of Auckland, Auckland 1142, New Zealand.
B Corresponding author. Email: j.reynisson@auckland.ac.nz
Australian Journal of Chemistry 71(8) 580-586 https://doi.org/10.1071/CH18225
Submitted: 18 May 2018 Accepted: 14 July 2018 Published: 21 August 2018
Abstract
Computer-aided drug design comprises several predictive tools, which can calculate various properties of the candidates under development. Proton affinity (PA) is related to pKa (the negative log of the acid dissociation constant (Ka)) one of the fundamental physical properties of drug candidates, determining their water solubility and thus their pharmacokinetic profile. The following questions therefore emerged: to what extent are PA predictions useful in drug design, and can they be reliably used to derive pKa values? Using density functional theory (DFT), it was established that for violuric acid, with three ionisation groups, the PAs correlate well with the measured pKas (R2 = 0.990). Furthermore, an excellent correlation within the amiloride compound family was achieved (R2 = 0.922). In order to obtain correlations for larger compound collections (n = 210), division into chemical families was necessary: carboxylic acids (R2 = 0.665), phenols (R2 = 0.871), and nitrogen-containing molecules (R2 = 0.742). These linear relationships were used to predict pKa values of 90 drug molecules with known pKas. A total of 48 % of the calculated values were within 1 logarithmic unit of the experimental number, but mainstream empirically based methods easily outperform this approach. The conclusion can therefore be reached that PA values cannot be reliably used for predicting pKa values globally but are useful within chemical families and in the event where a specific tautomer of a drug needs to be identified.
References
[1] Z. B. Maksić, B. Kovačević, R. Vianello, Chem. Rev. 2012, 112, 5240.| Crossref | GoogleScholarGoogle Scholar |
[2] S. Kolboe, J. Chem. Theory Comput. 2014, 10, 3123.
| Crossref | GoogleScholarGoogle Scholar |
[3] R. Casasnovas, J. Ortega-Castro, J. Frau, J. Donoso, F. Muñoz, Int. J. Quantum Chem. 2014, 114, 1350.
| Crossref | GoogleScholarGoogle Scholar |
[4] B. J. Smith, L. Radom, Chem. Phys. Lett. 1994, 231, 345.
| Crossref | GoogleScholarGoogle Scholar |
[5] J. J. Klicic, R. A. Friesner, S. Liu, W. C. Guida, J. Phys. Chem. A 2002, 106, 1327.
| Crossref | GoogleScholarGoogle Scholar |
[6] A. Klamt, F. Eckert, M. Diedenhofen, M. E. Beck, J. Phys. Chem. A 2003, 107, 9380.
| Crossref | GoogleScholarGoogle Scholar |
[7] S. Zhang, J. Baker, P. Pulay, J. Phys. Chem. A 2010, 114, 425.
| Crossref | GoogleScholarGoogle Scholar |
[8] S. Zhang, J. Baker, P. Pulay, J. Phys. Chem. A 2010, 114, 432.
| Crossref | GoogleScholarGoogle Scholar |
[9] S. Zhang, J. Comput. Chem. 2012, 33, 517.
| Crossref | GoogleScholarGoogle Scholar |
[10] T. Matsui, A. Oshiyama, Y. Shigeta, Chem. Phys. Lett. 2011, 502, 248.
| Crossref | GoogleScholarGoogle Scholar |
[11] M. J. Potter, M. K. Gilson, J. A. McCammon, J. Am. Chem. Soc. 1994, 116, 10298.
| Crossref | GoogleScholarGoogle Scholar |
[12] Y. H. Jang, L. C. Sowers, T. Cagin, W. A. Goddard, J. Phys. Chem. A 2001, 105, 274.
| Crossref | GoogleScholarGoogle Scholar |
[13] M. D. Liptak, G. C. Shields, J. Am. Chem. Soc. 2001, 123, 7314.
| Crossref | GoogleScholarGoogle Scholar |
[14] K. R. Adam, J. Phys. Chem. A 2002, 106, 11963.
| Crossref | GoogleScholarGoogle Scholar |
[15] J. H. Jensen, C. J. Swain, L. Oslen, J. Phys. Chem. A 2017, 121, 699.
| Crossref | GoogleScholarGoogle Scholar |
[16] A. M. Rebollar-Zepeda, A. Galano, RSC Adv. 2016, 6,
| Crossref | GoogleScholarGoogle Scholar |
[17] M. D. Tissandier, K. A. Cowen, W. Y. Feng, E. Gundlach, M. H. Cohen, A. D. Earhart, J. V. Coe, T. R. Tuttle, J. Phys. Chem. A 1998, 102, 7787.
| Crossref | GoogleScholarGoogle Scholar |
[18] V. S. Bryantsev, M. S. Diallo, W. A. Goddard Iii, J. Phys. Chem. B 2008, 112, 9709.
| Crossref | GoogleScholarGoogle Scholar |
[19] J. R. Pliego, Chem. Phys. Lett. 2003, 367, 145.
| Crossref | GoogleScholarGoogle Scholar |
[20] A. V. Marenich, R. M. Olson, C. P. Kelly, C. J. Cramer, D. G. Truhlar, J. Chem. Theory Comput. 2007, 3, 2011.
| Crossref | GoogleScholarGoogle Scholar |
[21] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009, 113, 6378.
| Crossref | GoogleScholarGoogle Scholar |
[22] A. Klamt, B. Mennucci, J. Tomasi, V. Barone, C. Curutchet, M. Orozco, F. J. Luque, Acc. Chem. Res. 2009, 42, 489.
| Crossref | GoogleScholarGoogle Scholar |
[23] J. Ho, Phys. Chem. Chem. Phys. 2015, 17, 2859.
| Crossref | GoogleScholarGoogle Scholar |
[24] P. S. Charifson, W. P. Walters, J. Med. Chem. 2014, 57, 9701.
| Crossref | GoogleScholarGoogle Scholar |
[25] J. M. Cabot, E. Fuguet, M. Rosés, ACS Comb. Sci. 2014, 16, 518.
| Crossref | GoogleScholarGoogle Scholar |
[26] A. C. Lee, G. M. Crippen, J. Chem. Inf. Model. 2009, 49, 2013.
| Crossref | GoogleScholarGoogle Scholar |
[27] I. V. Tetko, J. Gasteiger, R. Todeschini, A. Mauri, D. Livingstone, P. Ertl, V. A. Palyulin, E. V. Radchenko, N. S. Zefirov, A. S. Makarenko, V. V. Prokopenko, J. Comput. Aided Mol. Des. 2005, 19, 453.
| Crossref | GoogleScholarGoogle Scholar |
[28] I. V. Tetko, Drug Discov. Today 2005, 10, 1497.
| Crossref | GoogleScholarGoogle Scholar |
[29] VCCLAB, Virtual Computational Chemistry Laboratory 2005. Available at http://www.vcclab.org (accessed 1 August 2018)
[30] ChemAxon, Marvin 15.7.13.0 2015 (ChemAxon: Cambridge, MA). Available at http://www.chemaxon.com (accessed 1 August 2018)
[31] Biovia, Pipeline Pilot 2011 (Biovia: San Diego, CA).
[32] J. Tirado-Rives, W. L. Jorgensen, J. Chem. Theory Comput. 2008, 4, 297.
| Crossref | GoogleScholarGoogle Scholar |
[33] J. M. Moratal, A. Prades, M. Julve, J. Faus, Thermochim. Acta 1985, 89, 343.
| Crossref | GoogleScholarGoogle Scholar |
[34] B. R. Singh, R. Ghosh, J. Inorg. Nucl. Chem. 1981, 43, 727.
| Crossref | GoogleScholarGoogle Scholar |
[35] C. Bremard, G. Nowogrocki, S. Sueur, J. Chem. Soc., Dalton Trans. 1981, 1856.
| Crossref | GoogleScholarGoogle Scholar |
[36] M. G. Bock, H. B. Schlegel, G. M. Smith, J. Org. Chem. 1981, 46, 1925.
| Crossref | GoogleScholarGoogle Scholar |
[37] Y. C. Martin, Drug Discov. Today: Technol. 2018,
| Crossref | GoogleScholarGoogle Scholar |
[38] J. A. Dean, Lange’s Handbook of Chemistry 1979 (McGraw Hill Book Company: New York, NY).
[39] C. Zhou, Y. Jin, J. R. Kenseth, M. Stella, K. R. Wehmeyer, W. R. Heineman, J. Pharm. Sci. 2005, 94, 576.
| Crossref | GoogleScholarGoogle Scholar |
[40] D. M. Philipp, M. A. Watson, H. S. Yu, T. B. Steinbrecher, A. D. Bochevarov, Int. J. Quantum Chem. 2018, 118,
| Crossref | GoogleScholarGoogle Scholar |
[41] G. T. Balogh, B. Gyarmati, B. Nagy, L. Molnár, G. M. Keserű, QSAR Comb. Sci. 2009, 28, 1148.
| Crossref | GoogleScholarGoogle Scholar |
[42] J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev. 2005, 105, 2999.
| Crossref | GoogleScholarGoogle Scholar |
[43] E. P. L. Hunter, S. G. Lias, J. Phys. Chem. Ref. Data 1998, 27, 413.
| Crossref | GoogleScholarGoogle Scholar |
[44] M. Frisch, G. Trucks, H. Schlegel, G. Scuseria, M. Robb, J. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. Hratchian, A. Izmaylov, J. Bloino, G. Zheng, J. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. Montgomery, J. Peralta, F. Ogliaro, M. Bearpark, J. Heyd, E. Brothers, K. Kudin, V. Staroverov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. Millam, M. Klene, J. Knox, J. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. Stratmann, O. Yazyev, A. Austin, R. Cammi, C. Pomelli, J. Ochterski, R. Martin, K. Morokuma, V. Zakrzewski, G. Voth, P. Salvador, J. Dannenberg, S. Dapprich, A. Daniels, O. Farkas, J. Foresman, J. Ortiz, J. Cioslowski, D. Fox, Gaussian 09, revision D. 01 2010 (Gaussian, Inc.: Wallingford, CT).
[45] A. Becke, Phys. Rev. A 1988, 38, 3098.
| Crossref | GoogleScholarGoogle Scholar |
[46] A. Becke, J. Chem. Phys. 1993, 98, 5648.
| Crossref | GoogleScholarGoogle Scholar |
[47] C. Lee, W. Yang, R. Parr, Phys. Rev. B 1988, 37, 785.
| Crossref | GoogleScholarGoogle Scholar |
[48] P. Hariharan, J. Pople, Theor. Chim. Acta 1973, 28, 213.
| Crossref | GoogleScholarGoogle Scholar |
[49] M. J. Frisch, J. A. Pople, J. S. Binkley, J. Chem. Phys. 1984, 80, 3265.
| Crossref | GoogleScholarGoogle Scholar |
[50] M. W. Wong, Chem. Phys. Lett. 1996, 256, 391.
| Crossref | GoogleScholarGoogle Scholar |
[51] J. P. Perdew, Phys. Rev. B 1986, 33, 8822.
| Crossref | GoogleScholarGoogle Scholar |
[52] J. P. Perdew, K. Burke, Y. Wang, Phys. Rev. B 1996, 54, 16533.
| Crossref | GoogleScholarGoogle Scholar |
[53] J. P. Perdew, Y. Wang, Phys. Rev. B 1992, 45, 13244.
| Crossref | GoogleScholarGoogle Scholar |
[54] A. D. Becke, J. Chem. Phys. 1992, 97, 9173.
| Crossref | GoogleScholarGoogle Scholar |
[55] J. P. Perdew, J. A. Chevary, S. H. Vosko, K. A. Jackson, M. R. Pederson, D. J. Singh, C. Fiolhais, Phys. Rev. B 1992, 46, 6671.
| Crossref | GoogleScholarGoogle Scholar |
[56] J.-D. Chai, M. Head-Gordon, Phys. Chem. Chem. Phys. 2008, 10, 6615.
| Crossref | GoogleScholarGoogle Scholar |
[57] J. P. Perdew, K. Burke, M. Ernzerhof, Phys. Rev. Lett. 1996, 77, 3865.
| Crossref | GoogleScholarGoogle Scholar |
[58] C. Møller, M. S. Plesset, Phys. Rev. 1934, 46, 618.
| Crossref | GoogleScholarGoogle Scholar |
[59] See p. 143 in: J. Foresman, Exploring Chemistry with Electronic Structure Methods, 2nd edn 1996 (Gaussian Inc.: Pittsburgh, PA).
