DFT based QSARs for inhibitory activity of coumarins towards tumor-associated isoform (CA XII) of carbonic anhydrases

Yorulmaz N., EROĞLU E.

JOURNAL OF MOLECULAR STRUCTURE, cilt.1208, 2020 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 1208
  • Basım Tarihi: 2020
  • Doi Numarası: 10.1016/j.molstruc.2020.127844
  • Dergi Adı: JOURNAL OF MOLECULAR STRUCTURE
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Chimica, Compendex, INSPEC
  • Anahtar Kelimeler: Carbonic anhydrases, Coumarin, Sulfocoumarin, QSAR, LUMO, HOMO-1, EXPRESSION, HYPOXIA, TRANSMEMBRANE, CANCER, IX, PROTEIN, MECHANISM, DESIGN, POTENT, DOMAIN
  • Akdeniz Üniversitesi Adresli: Evet

Özet

Three QSAR models were developed from the calculated molecular descriptors of coumarins and sulfocoumarin and their inhibitory activities (pK(i)s) measured towards one (namely CA XII) of the isoforms of Carbonic Anhydrase (CA). An additional, one more selective QSAR model was also developed in which selective inhibitory activity of the compounds was defined as differences of inhibition constants between CA XII and CA II isoforms. The first one, the global model comprises 40/15 training/test compounds with the statistical parameters of R-2 = 0.797, Q(2) = 0.702, s(2) = 0.357, F = 26.796, R-pre.(2) = 0.783 and SE = 0.904. The second one, the coumarin model comprises 28/10 training/test compounds with the statistical parameters of R-2 = 0.742, Q(2) = 0.651, s(2) = 0.417, F = 16.586, R-pre.(2) = 0.887 and SE = 0.968. The third model, the sulfocoumarin model comprises 15/2 training/test compounds with the statistics of R-2 = 0.792, Q(2) = 0.730, s(2) = 0.289, F = 22.669, R-pre.(2) = 0.999 and SE = 0.353. The final model, the selective model consists of 21/5 training/test compounds with the statistical parameters of R-2 = 0.806, Q(2) = 0.693, s(2) = 0.683, F = 23.670, R-pre.(2) = 0.886 and SE = 0.353. Interpretation of descriptors, HOMO-1 and LUMO energies in the models let us to hypothesize that hydrolyzed coumarins and sulfocoumarins are electrostatically bound to the enzyme, thus they presumably play critical roles at the beginning e.g. in the hydrolyzing reaction step of the ligands which affects the overall binding free energy of the ligandisozyme complex. (C) 2020 Elsevier B.V. All rights reserved.