A comparative study of the binding modes of SLC-0111 and its analogues in the hCA II and hCA IX active sites using QM/MM, molecular docking, MM-GBSA and MD approaches.

Human carbonic anhydrase IX (hCA IX) is over-expressed in many tumor types and serves as an important target for the discovery of novel anticancer agents. However, development of compounds that can selectively inhibit hCA IX over its widespread cytosolic isoform human carbonic anhydrase II (hCA II) is a major challenge. This work focuses on recognizing the structural features of the hCA IX receptor that could help in achieving its selective inhibition. Tools such as protein structure alignment, rigid as well as flexible docking, QM/MM calculations and molecular dynamics simulations on SLC-0111, a selective hCA IX inhibitor, in complexation with each receptor, have been used to differentiate the receptor-ligand interactions in the two complexes. It is found that the ligand shows better binding to hCA IX due to stronger coordination to the Zn (II) ion. The ligand provides bidentate coordination through its negatively charged nitrogen and an oxygen of the sulfonamide zinc binding group. Binding energy calculations show that the potency of this ligand is due to the hydrophobic contacts, whereas the selectivity is due to the electrostatic interactions. Molecular docking and binding energy calculations for three different series of SLC-0111 analogs have identified a few molecules that show high potency and selectivity toward hCA IX. It is found that both hydrophobic and polar contacts contribute to the potency and selectivity of the ligands.