Virtual screening-driven identification of human carbonic anhydrase inhibitors incorporating an original, new pharmacophore |
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Authors: | Pala Nicolino Dallocchio Roberto Dessì Alessandro Brancale Andrea Carta Fabrizio Ihm Simone Maresca Alfonso Sechi Mario Supuran Claudiu T |
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Institution: | a Dipartimento di Scienze del Farmaco, Università di Sassari, Via Muroni 23/A, 07100 Sassari, Italy b CNR-Consiglio Nazionale delle Ricerche - Istituto di Chimica Biomolecolare, Sassari, 07040 Li Punti, Italy c Welsh School of Pharmacy, University of Wales, Cardiff CF10 3XF, Wales, Cardiff, UK d Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Km 188, Via della Lastruccia 3, I 50019 Sesto Fiorentino (Firenze), Italy |
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Abstract: | Combinated ligand- and pharmacophore-based virtual screening approaches were used to discover novel potential pharmacophores acting as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs). A free database of commercially available compounds was screened through drug-like filters using a four-point pharmacophore, and followed by docking calculation within the active site of an X-ray structure of isoform CA II. One compound, bearing a trifluoro-dihydroxy-propanone moiety, showed an interesting, selective inhibitory activity in low micromolar range against this isoform versus CA I. The chemical originality of this new pharmacophore can represent an important bioisosteric alternative to the sulfonamido-based functionalities, thus leading to the development of a new class of CAIs. |
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Keywords: | Human carbonic anhydrase CA inhibitors Virtual screening |
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