Although uncertainties exist about the mechanism of action of BCCs, increasing evidence about their toxicological profile strongly suggests that many can be safely administered to humans. Even stronger evidence exists regarding the capacity of BCCs to reach multiple targets that are involved in the treatment of common diseases. It seems fair to say that some BCCs will reach the market for medicinal use in the near future, not only for targeting microbial or neoplastic systems but also for acting on cell-signaling processes involved in many other disorders.

Because they represent attractive drug targets, adrenoceptors have been widely studied. Recent progress in structural data of β-adrenoceptors allows us to understand and predict key interactions in ligand recognition and receptor activation. Nevertheless, an important aspect of this process has only begun to be explored: the stabilization of a conformational state of these receptors upon contact with a ligand and the capacity of a ligand to influence receptor conformation through allosteric modulation, biased signaling, and selectivity. The aim of the present Perspective is to identify the well-defined orthosteric binding site and possible allosteric sites and to analyze the importance of the ligand-receptor interaction in the stabilization of certain receptor conformations. For this purpose, we have reviewed recent advances made through the use of X-ray data from ligand-β-adrenoceptor (including ADRB1 and ADRB2) crystal structures. Most importantly, implications in the medicinal chemistry field are explored in relation to drug design.

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The affinity of the classical β(2) adrenoceptor-selective inverse agonist ICI118,551 is notoriously lower for porcine β(2) adrenoceptors (p(2)βAR) than for human β(2) adrenoceptors (hβ(2)AR) but molecular mechanisms for this difference are still unclear. Homology 3-D models of pβ(2)AR can be useful in predicting similarities and differences, which might in turn increase the comparative understanding of ligand interactions with the hβ(2)AR. In this work, the pβ(2)AR amino acid sequence was used to carry out homology modeling. The selected pβ(2)AR 3-D structure was structurally and energetically optimized and used as a model for further theoretical study. The homology model of pβ(2)AR has a 3-D structure very similar to the crystal structures of recently studied hβ(2)AR. This was also corroborated by sequence identity, RMSD, Ramachandran map, TM-score and docking results. Upon performing molecular docking simulations with the AutoDock4.0.1 program on pβ(2)AR, it was found that a set of well-known β(2)AR ligands reach two distinct binding sites on pβ(2)AR. Whereas one of these sites is similar to that reported on the hβ(2)AR crystal structure, the other can explain some important experimental observations. Additionally, the theoretical affinity estimated for ICI118,551 closely agrees with affinities estimated from experimental in vitro data. The experimental differences between the human/porcine β(2)ARs in relation to ligand affinity can in part be elucidated by observations in this molecular modeling study.

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