Reverse Induced Fit-Driven MAS-Downstream Transduction: Looking for Metabotropic Agonists

Title:Reverse Induced Fit-Driven MAS-Downstream Transduction: Looking for Metabotropic Agonists

Volume: 24 Issue: 39

Author(s): Larissa Pernomian*, Mayara S. Gomes, Carlos H. Tomich de Paula da Silva and Joaquin M.C. Rosa

Affiliation:

• Department of Biosciences Applied to Pharmacy, Faculty of Pharmaceutical Sciences from Ribeirao Preto, University of Sao Paulo, P.O. Box: 14040-903, Ribeirao Preto, SP,Brazil

Keywords: MAS receptors, MAS-signalosome complex, reverse induced fit, canonical signaling, ligand binding domain, molecular modeling, metabotropic agonists, G Protein-coupled receptor.

Abstract: 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.

Cite this article as:

Pernomian Larissa *, Gomes S. Mayara , de Paula da Silva H. Tomich Carlos and Rosa M.C. Joaquin , Reverse Induced Fit-Driven MAS-Downstream Transduction: Looking for Metabotropic Agonists, Current Medicinal Chemistry 2017; 24 (39) . https://dx.doi.org/10.2174/0929867324666170912095306