title: Molecular modeling study for the binding of zonisamide and topiramate to the human mitochondrial carbonic anhydrase isoform VA.
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.
authors.affiliation: Istituto di Biostrutture e Bioimmagini-CNR, Via Mezzocannone 16, 80134 Naples, Italy.
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Vitale
authors.forename: Carlo
authors.initials: C
authors.lastname: Pedone
authors.forename: Pietro
authors.initials: P
authors.lastname: Amodeo
authors.forename: Jochen
authors.initials: J
authors.lastname: Antel
authors.forename: Michael
authors.initials: M
authors.lastname: Wurl
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Giuseppina
authors.initials: G
authors.lastname: De Simone
mesh_terms: D000595:Amino Acid Sequence; D002257:Carbonic Anhydrase Inhibitors / Q000378:metabolism*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D005632:Fructose / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D000077236:Topiramate; D000078305:Zonisamide
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D007555:Isoxazoles; D000077236:Topiramate; D005632:Fructose; D000078305:Zonisamide; D002256:Carbonic Anhydrases