QSAR and docking studies on inhibition of carbonic anhydrase tumorassociated isoenzyme IX with heterocyclic sulfonamides as cytotoxic agents

Mervat Hamed El-Hamamsy

Abstract

QSAR and docking studies on inhibition of carbonic anhydrase tumorassociated isoenzyme IX with heterocyclic sulfonamides as cytotoxic agents

Author(s): Mervat Hamed El-Hamamsy

Carbonic anhydrases (CAs) are metalloenzymes containing one zinc ion (Zn2+) per polypeptide chain. Sulfonamide derivatives incorporating substituted triazine ring have been investigated as excellent cytotoxic agents that inhibiting carbonic anhydrase tumor-associated isoenzyme IX.QSAR and docking studies for45 sulfonamide derivatives were performed. Twenty two QSAR models were constructed each model contain eight equations. The best of these models was chosen based on its statistical validation parameters where the R2 value was 0.98.Top model was returned based on six molecular descriptors; two fast descriptors, two spatial descriptors and two VAMP electrostatics descriptors. External validation of the developed model was governed by calculating the predicted biological activity and the residual values for training and test sets. These calculated values revealed a high prediction ability of our developed model. Molecular docking study aims to interpret the comparative differences in the binding interactions of these compounds at molecular level as inhibitors of CA IX.The sulfonamide (-SO2NH2) group of all docked compounds form hydrogen bond with Thr199 and is coordinated to zinc ion in the active site. Docking study revealed that the potency of the inhibitors was reduced by the presence of either bulky alkyl, orphenoxy substituent on the triazine ring. The potency was markedly enhanced by the presence of free aminoor amino acid substituents on triazine ring

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