Identification of potent human carbonic anhydrase IX inhibitors: a combination of pharmacophore modeling, 3D-QSAR, virtual screening and molecular dynamics simulations

Human carbonic anhydrase IX (hCA IX) is a promising target for the development of potential anticancer agents. In the current study, pharmacophore and 3D-QSAR models have been developed using SLC-0111 derivatives. The developed models have been further utilized for the virtual screening process to develop potent hCA IX inhibitors. Thirteen different models have been developed by employing various combinations of training and test set molecules. Based on this, a model, AADDR.135, comprising two H-bond acceptors, two H-bond donors and one aromatic ring, has been found as the best QSAR model. The proposed model exhibits high robustness (R (2) = 0.9789), with good predictive ability (Q (2) = 0.6872). An external library of drug-like compounds (similar to 10000 molecules) imported from the ZINC15 database has been screened over the model AADDR.135. In total, 1601 compounds were obtained as hits. Molecular docking studies and molecular dynamics simulations have been performed on the obtained hits and, based on these computations, two unique molecules have been identified as potential hCA IX inhibitors. These show higher binding energies compared to the parent molecule and its most potent analogue. Communicated by Ramaswamy H. Sarma