Selective Structure-Based Virtual Screening for Full and Partial Agonists of the β2 Adrenergic Receptor

Abstract

The recently solved high-resolution X-ray structure of the beta2 adrenergic receptor has been challenged for its ability to discriminate inverse agonists/antagonists from partial/full agonists. Whereas the X-ray structure of the ground state receptor was unsuitable to distinguish true ligands with different functional effects, modifying this structure to reflect early conformational events in receptor activation led to a receptor model able to selectively retrieve full and partial agonists by structure-based virtual screening. The use of a topological scoring function based on molecular interaction fingerprints was shown to be mandatory to properly rank docking poses and achieve acceptable enrichments for partial and full agonists only.

The structure of active opsin as a basis for identification of GPCR agonists by dynamic homology modelling and virtual screening assays

“…By the means of EFs, the active (B2AR ⁄ ) receptor model outperforms the inactive model (B2AR) in retrieving agonists. The moderate EF of B2AR for agonists agrees well with the results of other studies [36,38]. Nevertheless, B2AR ⁄ displays higher enrichment rates for agonists than B2AR at a cut-off of 0.5% and 1%.…”

“…As a measure of similarity, we used the Tanimoto coefficient [35] as a ligand score (tIFP). tIFPs were shown to be effective in other VLS studies with inactive GPCR models [27,36]. Only the highest scoring pose for each ligand was considered for the final ranking and discrimination into pharmacological classes.…”

Overlapping binding sites drive allosteric agonism and positive cooperativity in type 4 metabotropic glutamate receptors

“…The mutation L756S, which affects VU0155041 but not the other PAMs, corresponds to Ser211 in b1-adrenergic receptors or Ser203 (position 5.42) in the b2-adrenoceptor. This amino acid position was first predicted to be of prime importance for ligand binding and activation (22,57), which was later confirmed by the determination of the crystal structures in active and inactive states (24,58,59). Moreover, the interaction of this amino acid position, together with another serine in position 5.46, has been suggested as the determinant for full and partial agonism, as well as antagonism (24).…”

“…As stated in several structural studies, the binding site region of agonist-and antagonist-bound GPCR crystal structures exhibits minor conformational changes (22)(23)(24). The sequence of the D3 receptor was aligned with the one of rhodopsin by taking into account their structural superposition.…”

Structure-based discovery of β 2 -adrenergic receptor ligands

“…In retrospective docking screens of known agonists contained in the WOMBAT database, however, several were docked with scores that would have ranked them among the top 500 molecules of the million screened. Similarly, de Graaf and Rognan were able to successfully retrieve both agonists and antagonists when they docked to the ␤ 2 AR structure, using Interaction Fingerprint Scoring (28) for the ranking (29). Additionally, after changing the rotameric states of the side chains of only 2 residues (Ser-204 5.43 and Ser-207 5.46 ), it was possible to selectively retrieve agonists in the docking.…”