The Histamine H1-Receptor Antagonist Binding Site. A Stereoselective Pharmacophoric Model Based upon (Semi-)Rigid H1-Antagonists and Including a Known Interaction Site on the Receptor

Abstract

A new pharmacophoric model for the H1-antagonist binding site is derived which reveals that a simple atom to atom matching of compounds is not sufficient; in this model, interacting residues from the receptor need to be included. To obtain this model, the bioactive conformations of several (semi-)rigid classical histamine H1-receptor antagonists have been investigated (cyproheptadine, phenindamine, triprolidine, epinastine, mequitazine, IBF28145, and mianserine). In general, these antihistamines contain two aromatic rings and a basic nitrogen atom. A previously derived pharmacophoric model with the nitrogen position fixed relative to the two aromatic rings is now found not to be suitable for describing the H1-antagonist binding site. A procedure is described which allows for significant freedom in the position of the basic nitrogen of the histamine H1-antagonist. The area accessible to the basic nitrogen is confined to the region accessible to its counterion on the histamine H1-receptor, i.e., the carboxylate group of Asp116. The basic nitrogen is assumed to form an ionic hydrogen bond with this aspartic acid which C alpha- and C beta-carbons are fixed with respect to the protein backbone. Via this hydrogen bond, the direction of the acidic proton of the antagonist is taken into account. Within these computational procedures, an aspartic acid is coupled to the basic nitrogen of each H1-antagonist considered; the carboxylate group is connected to the positively charged nitrogen via geometric H-bonding restraints obtained from a thorough database search (CSD). Also to the basic nitrogen of the pharmacophore is coupled an aspartic acid (to yield our new template). In order to derive a model for the H1-antagonist binding site, the aromatic ring systems of the antagonists and template are matched according to a previously described procedure. Subsequently, the C alpha- and C beta-carbons of the aspartic acid coupled to the H1-antagonists are matched with those of the template in a procedure which allows the antagonist and the carboxylate group to adapt their conformation (and also their relative position) in order to optimize the overlap with the template. A six-point pharmacophoric model is derived which has stereoselective features and is furthermore able to distinguish between the so-called "cis"- and "trans"-rings mentioned in many (Q)SAR studies on H1-antagonists. Due to its stereoselectivity, the model is able to designate the absolute bioactive configuration of antihistamines such as phenindamine (S), epinastine (S), and IBF28145 (R). A further merit of this study is that a model is obtained which includes an amino acid from the receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

Mutational Analysis of the Antagonist-binding Site of the Histamine H1 Receptor

“…Predicition of Ligand-Receptor Interactions-H 1 antagonists were docked in the previously described three-dimensional receptor model of the guinea pig H 1 receptor (17), using the rigid H 1 antagonist pharmacophoric model of Ter Laak et al (18). This model describes the threedimensional topology of the cis-and trans-aromatic rings of cyproheptadine with respect to the positions of the C ␣ and C ␤ carbon atoms of an putative Asp residue from the receptor (see Fig.…”

“…Rotation was carried out along the C ␣ -C ␤ bond until cyproheptadine was positioned in the receptor in an energetically favorable orientation. The structure of the zwitterionic compounds acrivastine and d-cetirizine were built and optimized with Chem-X and subsequently docked into the H 1 receptor model onto the cyproheptadine template as described previously (18). Subsequently, all freely rotatable bonds in Lys 200 and in the side chains of the zwitterionic H 1 antagonist were taken into account in an extensive conformational analysis (MacroModel/AMBER force field (19)).…”

“…Previously, we also developed a three-dimensional computer model of the histamine H 1 receptor based on the homology with BR, incorporating the results obtained from mutagenesis studies on the agonist binding site (17). In the present study this computer model of the H 1 receptor was combined with a pharmacophoric model of the H 1 antagonistic binding site (18). This ligand-based model for the H 1 antagonistic binding site is based upon an interaction of the protonated amine function of various first generation, semi-rigid H 1 antagonists with an aspartate residue (Asp 116 in the guinea pig H 1 receptor) (18) and precisely positions the cis-and trans-aromatic rings of the H 1 antagonists relative to the C ␣ and C ␤ carbon atoms of this aspartate residue.…”

“…In the present study this computer model of the H 1 receptor was combined with a pharmacophoric model of the H 1 antagonistic binding site (18). This ligand-based model for the H 1 antagonistic binding site is based upon an interaction of the protonated amine function of various first generation, semi-rigid H 1 antagonists with an aspartate residue (Asp 116 in the guinea pig H 1 receptor) (18) and precisely positions the cis-and trans-aromatic rings of the H 1 antagonists relative to the C ␣ and C ␤ carbon atoms of this aspartate residue. Combining the three-dimensional receptor model and the ligand-based pharmacophoric model of the H 1 antagonist binding site resulted in the prediction of interactions of aromatic amino acids in TM IV and VI with the H 1 antagonists.…”

Modelling and mutation studies on the histamine H1-receptor agonist binding site reveal different binding modes for H1-agonists: Asp116 (TM3) has a constitutive role in receptor stimulation

“…The bioactive conformation of this compound was obtained from a previous study on the Hi-antagonistic binding site in which a stereoselective pharmacophore was derived by superimposing seven (semi-)rigid and potent antihistamines [19]. This H~-antagonist pharmacophore is represented by two aromatic rings and the positions of the C a and C ~ carbons of the aspartate from TM3 (Asp ~16) to which the basic nitrogen of antagonists is bound (see Fig.…”