title: Rational modelling of the voltage-dependent K+ channel inactivation by aminopyridines.
abstract: A functional model for the in vitro inactivation of voltage-dependent K(+) channels is developed. The model expresses the activity as a function of the aminopyridine pK(a), the interaction energy with the receptor, and a quotient of partition functions. Molecular quantum similarity theory is introduced in the model to express the activity as a function of the principal components of the similarity matrix for a series of agonists. To validate the model, a set of five active (protonated) aminopyridines is considered: 2-aminopyridine, 3-aminopyridine, 4-aminoquinoleine, 4-aminopyridine, and 3,4-diaminopyridine. A regression analysis of the model gives good results for the variation of the observed activity with the overlap similarity index when pyridinic rings are superposed. The results support the validity of the model, and the hypothesis of a ligand-receptor entropy variation depending mainly on the nature of the ligand. In addition, the results suggest that the pyridinic ring must play an active role in the interaction with the receptor site. This interaction with the protonated pyridinic nitrogen can involve a cation-pi interaction or a donor hydrogen bond. The amine groups, at different relative positions of the pyridinic nitrogen, can form one or more hydrogen bonds due to the C(4) symmetry of the inner part of the pore in the K(+) channel.
authors.affiliation: Grupo de Qui;mica Computacional, Escuela Superior de Informática, Universidad de Castilla-La Mancha, Paseo de la Universidad 4, 13071, Ciudad Real, Spain. quimcom@uclm.es
authors.forename: Alfonso
authors.initials: A
authors.lastname: Niño
authors.forename: Camelia
authors.initials: C
authors.lastname: Muñoz-Caro
authors.forename: Ramón
authors.initials: R
authors.lastname: Carbó-Dorca
authors.forename: Xavier
authors.initials: X
authors.lastname: Gironés
mesh_terms: D000631:Aminopyridines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D019277:Entropy; D006860:Hydrogen Bonding; D008024:Ligands; D016014:Linear Models; D008954:Models, Biological; D015394:Molecular Structure; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011522:Protons
chemical_list: D000631:Aminopyridines; D008024:Ligands; D024642:Potassium Channels, Voltage-Gated; D011522:Protons