Identification of potential tumour-associated carbonic anhydrase isozyme IX inhibitors: atombased 3D-QSAR modelling, pharmacophore-based virtual screening and molecular docking studies

Kumar, Avinash and Rathi, Ekta and Kini, Suvarna G (2020) Identification of potential tumour-associated carbonic anhydrase isozyme IX inhibitors: atombased 3D-QSAR modelling, pharmacophore-based virtual screening and molecular docking studies. Journal of Biomolecular Structure and Dynamics, 38 (7). pp. 2156-2170. ISSN 0739-1102

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Abstract

Tumour hypoxia results in dramatic changes in the gene expression, proliferation and survival of tumour cells. The tumour cells shift towards anaerobic glycolysis which results in change of pH in their microenvironment. In response to this stress, over expression of carbonic anhydrase IX (CA IX) genes is observed in many solid tumours. So, selective inhibition of CA IX can be a promising target for anticance drugs. In this work in silico tools like atom-based 3D-QSAR modelling, harmacophore-based virtual screening and molecular docking were used to identify potential CA IX inhibitors. Based on the training set used in the QSAR model, twenty pharmacophore models were generated. Out of these, HHHR_1, AHHR_1, DHHHR_1, AHHHR_1 model was used to screen a database of 1,50,000 compounds retrieved from ZINC 15 database. R2 and Q2 was 0.9864 and 0.8799, respectively, for the developed QSAR model. 163 compounds showed a phase screen score above 2.4 in which ZINC02260669 was the highest ranked (screen score, 2.852058) compound in all the four models. Built QSAR model was used to predict the activity of all these 163 compounds and ZINC72370966 showed the highest predicted activity with pKi value of 7.649. These compounds were docked against CA IX (human) protein (PDB ID 5FL6) and molecular docking results showed favourable binding interactions for the best ten identified hits. This work gives design insights and some potential scaffolds which can be developed as CA IX inhibitors.

Item Type: Article
Uncontrolled Keywords: Carbonic anhydrase isozyme IX; molecular docking; pharmacophore; QSAR; tumour; virtual screening.
Subjects: Pharmacy > MCOPS Manipal > Pharmaceutical Chemistry
Depositing User: KMC Library
Date Deposited: 01 Jul 2020 06:59
Last Modified: 01 Jul 2020 06:59
URI: http://eprints.manipal.edu/id/eprint/155150

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