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Ligand‐based design, virtual screening, and ADME/T‐based profiling on a dataset of 1,3,5‐triazine‐substituted benzene sulfonamides as carbonic anhydrase inhibitors
Author(s) -
Saluja Amrita K.,
Tiwari Meena,
Kumar Surendra
Publication year - 2014
Publication title -
journal of chemometrics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.47
H-Index - 92
eISSN - 1099-128X
pISSN - 0886-9383
DOI - 10.1002/cem.2579
Subject(s) - chemistry , quantitative structure–activity relationship , carbonic anhydrase , adme , carbonic anhydrase ii , lipinski's rule of five , virtual screening , docking (animal) , stereochemistry , triazine , ligand (biochemistry) , pharmacophore , computational chemistry , combinatorial chemistry , enzyme , organic chemistry , in silico , biochemistry , medicine , receptor , nursing , in vitro , gene
A quantitative structure–activity relationship (QSAR) analysis was performed on a dataset of 62 (1,3,5‐triazine‐substituted) benzene sulfonamides as carbonic anhydrase II and IX inhibitors using simulated annealing‐based multiple linear regression analysis. The selected QSAR model for carbonic anhydrase II inhibition (cross‐validated Q 2 = 0.689,r pred 2 = 0.780 ,r m 2 = 0.565 ) showed that aromaticity, lipophilicity, electronegativity, and molecular projection in the XZ plane influence the activity, whereas that for carbonic anhydrase IX inhibition (cross‐validated Q 2 = 0.767,r pred 2 = 0.841 ,r m 2 = 0.690 ) showed that activity was influenced by hydrophilicity, linker between the aromatic rings, electronegativity, and molecular weight. The QSAR model selected was internally and externally validated to define its predictability. Activity prediction of an external dataset containing nine compounds (within the same sphere of applicability) was performed to prove the models' specificity, selectivity, and sensitivity. The hypothesis in the form of the QSAR model was used for ligand‐based virtual screening on the ZINC database to obtain some potential hits. Similarly, docking studies on screened hits showed that the molecules interact and orient at the catalytic site in a way similar to acetazolamide. Additionally, an absorption, distribution, metabolism, excretion, and toxicity screening was also performed, and results showed that most of the compounds that can be possible drug candidates obey the Lipinski rule of five and Jorgensen rule of three. Copyright © 2013 John Wiley & Sons, Ltd.