Background: Protective effects of MAS activation have spurred clinical interests in
developing MAS agonists. However, current bases that drive this process preclude that physiological
concentrations of peptide MAS agonists induce an atypical signaling that does not reach
the metabotropic efficacy of constitutive activation. Canonical activation of MAS-coupled G proteins
is only achieved by supraphysiological concentrations of peptide MAS agonists or physiological
concentrations of chemically modified analogues. These pleiotropic differences are because
of two overlapped binding domains: one non-metabotropic site that recognizes peptide
agonists and one metabotropic domain that recognizes modified analogues.
Objective: It is feasible that supraphysiological concentrations of peptide MAS agonists undergo
to chemical modifications required for binding to metabotropic domain. Receptor oligomerization
enhances pharmacological parameters coupled to metabotropic signaling. The formation of
receptor-signalosome complex makes the transduction of agonists more adaptive. Considering
the recent identification of MAS-signalosome, we aimed to postulate the reverse induced fit hypothesis
in which MAS-signalosome would trigger chemical modifications required for agonists
bind to MAS metabotropic domain.
Methods: Here we cover rational perspectives for developing novel metabotropic MAS agonists
in the view of the reverse induced-fit hypothesis.
Results: Predicting a 3D model of MAS metabotropic domain may guide the screening of chemical
modifications required for metabotropic efficacy. Pharmacophore-based virtual screening
would select potential metabotropic MAS agonists from virtual libraries from human proteome.
Conclusions: Rational perspectives that consider reverse induced fit hypothesis during MAS activation
for developing metabotropic MAS agonists represents the best approach in providing
MAS ligands with constitutive efficacy at physiological concentrations.