Pharmacophore Modeling and 3D QSAR Studies of Novel Human Carbonic Anhydrase IX Inhibitors

Kalyan   K.   Sethi; Saurabh   M.   Verma

Abstract

Carbonic anhydrase (CA) IX is considered as a potential target for cancer therapy. In order to identify new scaffolds compounds and use them for designing novel CA IX inhibitors, herein 3D pharmacophore hypotheses had been established. Alignment and Scoring Engine (PHASE) software has been used to develop ligand-based pharmacophore model using a large set of 36 different aromatic/ heterocyclic sulfamates carbonic anhydrase inhibitors, such as CA IX chosen for the present study. In this study pharmacophore model was developed by downloading a large set of 36 ligands with Ki (nM) value from binding database. Ki ranged from >24 were considered as inactive and <24 nM were considered as active and found ligand 3ba as a templet molecule for the dataset chosen by PHASE. PHASE module of Schrodinger revealed the two hydrogen-bond acceptors, two hydrogen-bond donors, and one hydrophobic aromatic ring (AADDR.47) as crucial molecular features that predict binding-affinity of ligands to the hCA IX isoenzyme inhibition. The validity of each model predicted from the calculated correlation coefficient (q²) of 0.7049 and predicted squared correlation coefficient Q² (r² _pred) of 0.6280 for the test set confirms the good predictability of the QSAR model. The variant with a site score 0.89, vector score 0.952, volume score 0.654, and survival score of 3.497 was considered to be the best pharmacophore hypothesis. The information rendered by pharmacophore and 3D-QSAR modeling can provide guidelines for the development of improved hCA IX inhibitors as leads for various types of metastatic cancers including those of cervical, renal, breast and head and neck origin.

Keywords: Drug design, Carbonic anhydrase IX inhibitors, 3D-QSAR, Sulfamates, Pharmacophore, PHASE, AADDR.47.

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