Structural investigation of isatin-based benzenesulfonamides as carbonic anhydrase isoform IX inhibitors endowed with anticancer activity using molecular modeling approaches

Carbonic anhydrase IX (CA IX) is a trans membrane protein that highly expressed in hypoxia tumor cells. Selective inhibition of CA IX isoenzyme by small molecule CA inhibitors such as sulfonamide derivatives has blocked tumor growth in multiple cancer models and CA IX is a promising target for cancer therapy. In the present research, molecular modeling investigations, such as CoMFA, CoMFA-RF, CoMSIA and HQSAR, molecular docking molecular and dynamics (MD) simulations were carried out on a series of isatin-based benzenesulfonamide derivatives as CA IX inhibitors, which was split randomly into training (n = 43) and test set (n = 15). The statistical qualities of generated models were justified by internal and external validation, i.e., cross-validated correlation coefficient (q(2)), non-cross validated correlation coefficient (r(ncv)(2)) and predicted correlation coefficient (r(pred)(2)), respectively. The CoMFA (q(2), 0.712; r(ncv)(2), 0.848; r(pred)(2), 0.908), CoMFA-RF (q(2), 0.719; r(ncv)(2), 0.890; r(pred)(2), 0.926), CoMSIA (q(2), 0.717; r(ncv)(2), 0.841; r(pred)(2), 0.915) and HQSAR models (q(2), 0.782; r(ncv)(2), 0.849; r(pred)(2), 0.935) for training and test set of CA IX inhibition yielded significant statistical findings. Several external parameters, such as, Q(F1)(2), Q(F2)(2), Q(F3)(2) and CCC were 0.907, 0.901, 0.716 and 0.954 (CoMFA); 0.926, 0.907, 0.715 and 0.959 (CoMFA-RF); 0.914, 0.909, 0.738 and 0.952 (CoMSIA) and 0.937, 0.933, 0.808 and 0.962 (HQSAR), respectively. Therefore, these QSAR models were excellent, robust and had better predictive capability. Contour maps of all models were generated and validated by molecular docking and molecular dynamics simulation studies, that the steric, hydrophobic and hydrogen bonding fields are crucial in these models for improving the binding affinity and determine of structure- activity relationship. The docking results showed that Gln92, His94, His96, His119 and Thr200 were important residues in the active site of CA IX. The primary sulfonamide group of these derivatives as scaffold and the isatin tail scaffold groups as hydrophobic and electrostatic parts are essential for improving CA IX protein inhibitory activity. Based on these results, five new CA IX inhibitors were designed by the molecular models which showed good potential activity and reasonably good ADMET profiles and could selectively inhibit hCA IX. These theoretical results are possibly beneficial to rational design of new potent CA IX inhibitors with enhanced activity to treat cancer. (C) 2020 Elsevier B.V. All rights reserved.

Automated summary

In this study, various molecular modeling techniques were used to investigate isatin-based benzenesulfonamide derivatives as CA IX inhibitors. The models showed significant statistical findings for CA IX inhibition and provided valuable insights for improving the binding affinity and structure-activity relationship. Furthermore, the study identified important residues in the active site of CA IX and essential structural features for enhancing inhibitory activity, leading to the design of potential new inhibitors with improved activity for cancer treatment.