A three-dimensional quantitative structure-affinity relationship study (3D-QSAR), using the comparative molecular field analysis (CoMFA) method, and subsequent computational simulation of ligand recognition have been successfully applied to explain the binding affinities for the 5-HT4 receptor (5-HT4R) of a series of benzimidazole-4-carboxamides and carboxylates derivatives 1-24. The Ki values of these compounds are in the range from 0.11 to 10 000 nM. The derived 3D-QSAR model shows high predictive ability (q2 = 0.789 and r2 = 0.997). Steric (contribution of 43.5%) and electrostatic (50.3%) fields and solvation energy (6.1%) of this novel class of 5-HT4R antagonists are relevant descriptors for structure-activity relationships. Computational simulation of the complexes between the benzimidazole-4-carboxamide UCM-21195 (5) and the carboxylate UCM-26995 (21) and a 3D model of the transmembrane domain of the 5-HT4R, constructed using the reported crystal structure of rhodopsin, have allowed us to define the molecular details of the ligand-receptor interaction that includes (i) the ionic interaction between the NH group of the protonated piperidine of the ligand and the carboxylate group of Asp3.32, (ii) the hydrogen bond between the carbonyl oxygen of the ligand and the hydroxyl group of Ser5.43, (iii) the hydrogen bond between the NH group of Asn6.55 and the aromatic ring of carboxamides or the ether oxygen of carboxylates, (iv) the interaction of the electron-rich clouds of the aromatic ring of Phe6.51 and the electron-poor hydrogens of the carbon atoms adjacent to the protonated piperidine nitrogen of the ligand, and (v) the π-σ stacking interaction between the benzimidazole system of the ligand and the benzene ring of Tyr5.38. Moreover, the noticeable increase in potency at the 5-HT4R sites, by the introduction of a chloro or bromo atom at the 6-position of the aromatic ring, is attributed to the additional electrostatic and van der Waals interaction of the halogen atom in a small cavity located between transmembrane domains 5 and 6.
|Journal||Journal of Medicinal Chemistry|
|Publication status||Published - 24 Oct 2002|