Characterization of β3-adrenergic receptor: determination of pharmacophore and 3D QSAR model for β3 adrenergic receptor agonism

Abstract

The beta3-adrenoreceptor (beta3-AR) has been shown to mediate various pharmacological and physiological effects such as lipolysis, thermogenesis, and intestinal smooth muscle relaxation. It also plays an important role in glucose homeostasis and energy balance. Molecular modeling studies were undertaken to develop predictive pharmacophoric hypothesis and 3D-QSAR model, which may explain variations in beta3-AR agonistic activity in terms of chemical features and physicochemical properties. The two softwares, CATALYST for pharmacophoric alignment and APEX-3D for 3D-QSAR modeling were used to establish the structure activity relationships for beta3-AR agonistic activity. Among the several statistically significant models, the selection of the best pharmacophore and 3D-QSAR model was based on its ability to estimate the activity of external test sets of similar and different structural types along with the reasonable consistency of the model with the limited information of the active site of beta3-AR. The final 3D-QSAR model was derived using the pharmacophoric alignments from the hypothesis which consisted of four chemical features: basic or positive ionizable feature on the nitrogen of the aryloxypropylamino group, two ring aromatic features corresponding to the phenyl ring of the phenoxide and the benzenesulphonamido groups and a hydrogen-bond donor (HBD) in the vicinity of the nitrogen atom of the benzenesulphonamido group with the most active molecule mapping in an energetically favorable extended conformation. This hypothesis was in agreement with the site directed mutagenesis studies on human beta3-AR and correlated well the observed and estimated activity both in, training and both the external test sets. It also mapped reasonably well to six beta3-AR agonists of different structural classes under clinical development and thus this hypothesis may have a universal applicability in providing a powerful template for virtual screening and also for designing new chemical entities (NCEs) as beta3-AR agonists.

The Tertiary Amine Nitrogen Atom of Piperazine Sulfonamides as a Novel Determinant of Potent and Selective β3‐Adrenoceptor Agonists

“…Hence, efforts to identify clues for b 3 -AR agonist activity/selectivity, as well as to address the abovementioned issues are required. [15,23,24] As far as oral bioavailability is concerned, most of the orally administered drugs can be assumed to be passively transported through the intestinal cell membrane. The main predictive parameter for drug absorption is the calculated logarithm of the n-octanol/water partition coefficient (Clog P, Table 1), which represents a criterion to grade the extent of drug absorption from poor to high.…”

“…Furthermore, the strength of their interactions with specific amino acids of the b 3 -AR binding site would be modified, and their capacity to form hydrogen bonds would be compromised. [23] In addition, their pharmacokinetic profile could possibly be affected.…”

Pharmacophore modeling of some novel indole β-diketo acid and coumarin-based derivatives as HIV integrase inhibitors

“…Computational methodology for 3D-QSAR Pharmacophore modeling presents a qualitative picture of the geometry of the active site by identifying the chemical features for binding of ligands and their spatial arrangements in 3D space (Axe et al, 2006;Prathipati and Saxena, 2005). In this study, pharmacophore modeling was carried out using Pharmacophore Alignment and Scoring Engine PHASE.…”

Three-dimensional QSAR and pharmacophore mapping of biphenyl benzoic acid derivatives as selective human β3-adrenergic receptor agonists

“…Pharmacophore modeling presents a qualitative picture of the geometry of the active site by identifying the features for binding of ligands and their spatial arrangements (Axe et al, 2006;Prathipati and Saxena, 2005). In this study, pharmacophore modeling was carried out using Pharmacophore Alignment and Scoring Engine (PHASE).…”