http://www.cnr.it/ontology/cnr/individuo/prodotto/ID168794

Molecular modeling study for the binding of zonisamide and topiramate to the human mitochondrial carbonic anhydrase isoform VA (Articolo in rivista)

Type

Prodotto della ricerca (Classe)
Articolo in rivista (Classe)

Label

Molecular modeling study for the binding of zonisamide and topiramate to the human mitochondrial carbonic anhydrase isoform VA (Articolo in rivista) (literal)

Anno

2007-01-01T00:00:00+01:00 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi

10.1016/j.bmc.2007.03.070 (literal)

Alternative label

Vitale RM; Pedone C; Amodeo P; Antel J; Wurl M; Scozzafava A; Supuran CT; De Simone G (2007)
Molecular modeling study for the binding of zonisamide and topiramate to the human mitochondrial carbonic anhydrase isoform VA
in Bioorganic & medicinal chemistry (Print); Academic Press Ltd., Elsevier Science Ltd., London (Regno Unito)
(literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori

Vitale RM; Pedone C; Amodeo P; Antel J; Wurl M; Scozzafava A; Supuran CT; De Simone G (literal)

Pagina inizio

4152 (literal)

Pagina fine

4158 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume

15 (literal)

Rivista

Bioorganic & medicinal chemistry (Rivista)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo

12 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#descrizioneSinteticaDelProdotto

Pubblicazione su rivista scientifica (literal)

Note

ISI Web of Science (WOS) (literal)
Scopu (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni

aIstituto di Biostrutture e Bioimmagini-CNR, Via Mezzocannone 16, 80134 Naples, Italy bDipartimento delle Scienze Biologiche, University of Naples ''Federico II'', Via Mezzocannone 16, 80134 Naples, Italy cIstituto di Chimica Biomolecolare-CNR, Comprensorio Olivetti, I-80078, Pozzuoli (Naples), Italy dSolvay Pharmaceuticals Laboratories, Hans Bo¨ ckler-Allee 20, D-30173 Hannover, Germany eUniversita` degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy (literal)

Titolo

Molecular modeling study for the binding of zonisamide and topiramate to the human mitochondrial carbonic anhydrase isoform VA (literal)

Abstract

Abstract--Zonisamide and topiramate are two antiepileptic drugs known to induce weight loss in epilepsy patients. These molecules were recently shown to act as carbonic anhydrase (CA) inhibitors, being presumed that the weight loss may be due to the inhibition of the mitochondrial isozymes CA VA and CA VB involved in metabolic processes, among which lipid biosynthesis. To better understand the interaction of these compounds with CAs, here, we report a homology modeling and molecular dynamics simulations study on their adducts with human carbonic anhydrase VA (hCA VA). According to our results, in both cases the inhibitor sulfamate/sulfonamide moiety participates in the canonical interactions with the catalytic zinc ion, whereas the organic scaffold establishes a large number of van der Waals and polar interactions with the active site cleft. A structural comparison of these complexes with the corresponding homologues with human carbonic anhydrase II (hCA II) provides a rationale to the different affinities measured for these drugs toward hCA VA and hCA II. In particular, our data suggest that a narrower active site cleft, together with a different hydrogen bond network arrangement of hCA VA compared to hCA II, may account for the different Kd values of zonisamide and topiramate toward these physiologically relevant hCA isoforms. These results provide useful insights for future design of more isozyme-selective hCA inhibitors with potential use as anti-obesity drugs possessing a novel mechanism of action. (literal)

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