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Reverse Induced Fit-Driven MAS-Downstream Transduction: Looking for Metabotropic Agonists.
Larissa Pernomian1, Mayara S Gomes1, Carlos H Tomich de Paula da Silva1
1Department 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.
Current Medicinal Chemistry
|September 14, 2017
Summary
Developing novel MAS agonists requires understanding their binding domains. The reverse induced fit hypothesis suggests MAS-signalosome complexes can modify agonists for enhanced metabotropic signaling at physiological concentrations.
Area of Science:
- Pharmacology
- Biochemistry
- Drug Discovery
Background:
- MAS receptor activation shows protective effects, driving interest in MAS agonists.
- Current peptide MAS agonists at physiological concentrations exhibit atypical signaling, lacking metabotropic efficacy.
- Achieving canonical MAS-coupled G protein activation requires supraphysiological agonist concentrations or modified analogues, due to distinct binding domains.
Purpose of the Study:
- To explore the feasibility of supraphysiological peptide MAS agonists undergoing modifications for metabotropic domain binding.
- To investigate the role of receptor oligomerization and MAS-signalosome complex formation in enhancing metabotropic signaling.
- To postulate the reverse induced fit hypothesis, where MAS-signalosome triggers agonist modifications for binding to the MAS metabotropic domain.
Main Methods:
- Rational perspectives for developing novel metabotropic MAS agonists based on the reverse induced-fit hypothesis.
- Predicting a 3D model of the MAS metabotropic domain to guide screening for necessary chemical modifications.
- Employing pharmacophore-based virtual screening against human proteome libraries to identify potential metabotropic MAS agonists.
Main Results:
- A 3D model of the MAS metabotropic domain can guide the identification of required chemical modifications for metabotropic efficacy.
- Virtual screening utilizing pharmacophore models can identify potential metabotropic MAS agonists from extensive human proteome libraries.
- The study provides a framework for rational drug design targeting the MAS receptor.
Conclusions:
- Developing metabotropic MAS agonists with constitutive efficacy at physiological concentrations is best achieved through rational perspectives incorporating the reverse induced fit hypothesis.
- This approach facilitates the design of MAS ligands that can effectively engage the metabotropic binding site.
- Understanding MAS receptor-ligand interactions at a molecular level is crucial for therapeutic advancements.
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