MODELLING DRUG-RECEPTOR INTERACTIONS IN AN AVERAGE BINDING SITE FOR NK2

Abstract

A tentative procedure applied to the search for a new antagonist of the neurokinin A (NKA) is presented. In parallel a tentative 3-D model of the NK2 receptor was created, using bacteriorhodopsin (BRD) as a template. The residue substitutions were performed in BRD to obtain the sequence for NK2R_H and the seven a-helical segments were optimized forcing the a-helical backbone to match the corresponding aligned pans of BRD, while the arrangements of the side chains were model built based on available site-directed mutagenesis studies. Constrained MM and molecular dynamics simulations were carried out such a way to permit formation of H-bonds between low energy conformers of the known drugs and aminoacid residues in the receptor site. The Connolly surface for each ligand allowed to determine an "average" binding site in which all the low energy conformers, of known and prospective drugs, were docked and classified according to a statistical index. The whole procedure was repeated exploiting the lately published structure of an actual G protein coupled receptor as a better template, thus producing a cavity in the binding site to dock directly the drugs. Corollary validations of the force fields used are also mentioned. In addition intra- and intermolecular interactions suitable to produce more active drugs were evaluated.