title: Quantitative Characterization of the Interaction Space of the Mammalian Carbonic Anhydrase Isoforms I, II, VII, IX, XII, and XIV and their Inhibitors, Using the Proteochemometric Approach.
abstract: The critical role of carbonic anhydrases in different physiological processes has put this protein family at the center of attention, challenging major diseases like glaucoma, neurological disorders such as epilepsy and Alzheimer's disease, obesity, and cancers. Many QSAR/QSPR (quantitative structure-activity/property relationship) researches have been carried out to design potent carbonic anhydrase inhibitors (CAIs); however, using inhibitors with no selectivity for different isoforms can lead to major side-effects. Given that QSAR/QSPR methods are not capable of covering multiple targets in a unified model, we have applied the proteochemometric approach to model the interaction space that governs selective inhibition of different CA isoforms by some mono-/dihydroxybenzoic acid esters. Internal and external validation methods showed that all models were reliable in terms of both validity and predictivity, whereas Y-scrambling assessed the robustness of the models. To prove the applicability of our models, we showed how structural changes of a ligand can affect the selectivity. Our models provided interesting information that can be useful for designing inhibitors with selective behavior toward isoforms of carbonic anhydrases, aiding in their selective inhibition.
authors.affiliation: Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, PO Box 13145-1365 Tehran, Iran.
authors.forename: Behnam
authors.initials: B
authors.lastname: Rasti
authors.affiliation: Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, PO Box 13145-1365 Tehran, Iran.
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Karimi-Jafari
authors.affiliation: Department of Analytical Chemistry, School of Chemistry, College of Science, University of Tehran, PO Box 13145-1365 Tehran, Iran.
authors.forename: Jahan B
authors.initials: JB
authors.lastname: Ghasemi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D008024:Ligands; D020033:Protein Isoforms; D002256:Carbonic Anhydrases
keywords: carbonic anhydrase; cytosolic isoforms; proteochemometrics; selective inhibition; transmembrane isoforms