జర్నల్ ఆఫ్ కార్సినోజెనిసిస్ & మ్యూటాజెనిసిస్

నైరూప్య

Receptor Chemoprint Derived Pharmacophore Model for Development of CAIX Inhibitors

Prakash Amresh, Kundan Kumar, Asimul Islam, Md. Imtaiyaz Hassan and Faizan Ahmad

Background: Carbonic anhydrase IX (CAIX) is an attractive target for anticancer therapy because it is selectively overexpressed in tumor cells. Various CAs’ inhibitors (sulfonamides/sulfaumates and coumarins) are reported as promising anti-cancer agents, showed appreciable affinity and selectivity. Novel chemical scaffolds with improved pharmacological properties are essential for the development of safe and potent CAIX inhibitors. Materials and methods: Crystal structure of CAIX with its inhibitors revealed critical residues of CAIX that interacts to inhibitor(s). These information was used to design a receptor-chemoprint based pharmacophore model. In silico pharmacokinetic assays were carried for novel hits with both ADMET and TOPKAT tools of Discovery Studio 3.5. Results: Pharmacophore model consists of one hydrogen bond donor, three hydrogen bond acceptors, and two hydrophobic moieties which are defined as essential feature for CAIX inhibitors. Virtual screening of ZINC chemical databases leads to identification of 1242 hits, having pharmacophore fit score ≥ 0.95. These hits were subsequently subjected to molecular docking analysis but they are limited to 321 only. Conclusion: Based on consensus scoring values, critical interactions with active site residues, and predicted activity values, five compounds (ZINC03363328, ZINC08828920, ZINC12941947, ZINC03622539 and ZINC16650541) are proposed as possible lead for CAIX inhibitor. Present study suggests that a conceptual adjustment of these hits may lead to rational design of novel and potent CAIX inhibitor.