Banca de QUALIFICAÇÃO: GABRIELA DE LIMA MENEZES

Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.
STUDENT : GABRIELA DE LIMA MENEZES
DATE: 20/11/2023
TIME: 09:00
LOCAL: Google Meet, https://meet.google.com/xmg-tfyg-par
TITLE:

Molecular and quantum analysis of the binding modes and affinities of melatonin and its analogues with MT1 and MT2 receptors

KEY WORDS:

Molecular Dynamics; DFT; Sleep Disorder; MFCC; Melatonin Receptors; Molecular Docking

PAGES: 57
BIG AREA: Ciências Biológicas
AREA: Biologia Geral
SUMMARY:

Currently, there is a high prevalence of sleep disorders in the world, affecting about 30% of the global population. Therapeutic and non-therapeutic interventions are available for the treatment of such disorders. Among the therapeutic interventions, the most used ones - for providing greater efficacy - involve the use of benzodiazepines (BDZ) and non-benzodiazepines (n-BZD), however the adverse effects observed with the use of these classes of drugs raise questions about their extended use. As an option to the use of these classes of medications, there are drugs that act on melatonin receptors MT1 and MT2. These proteins are G protein-coupled receptors that mediate the effects of melatonin, a hormone involved in circadian rhythms and other physiological functions. Understanding the molecular interactions between these receptors and their ligands is crucial for the development of new therapeutic agents with lower adverse effects than those observed with the use of BDZ and n-BZD. In this study, we used molecular docking, molecular dynamics (MD) simulations, hybrid calculations (QM/MM) and quantum mechanics (QM/DFT) to investigate the binding modes and affinities of three ligands of MT1 and MT2 receptors: melatonin (MLT), ramelteon (RMT) and 2-phenylmelatonin (2-PMT) with both receptors. Based on the results, it was possible to obtain complex of MT1 and MT2 with MLT, not yet available experimentally. QM/MM and QM analysis pointed out that the models of complexes formed with MLT have affinities consistent with data from the literature. Together with the QM analysis of the structures with RMT and 2-PMT experimentally resolved, we identified key amino acids that contributed to the receptor-ligand interactions, such as Gln181/194, Phe179/192 and Asn162/175, which are conserved in both receptors. In addition, we described new important interactions with Gly108/Gly121, Val111/Val124 and Val191/Val204. Our results provide insights into the structural and energetic determinants of receptor-ligand recognition and suggest potential strategies for designing more optimized molecules. This study enhances our understanding of receptor-ligand interactions and offers implications for the development of future drugs

COMMITTEE MEMBERS:
Externo à Instituição - ROOSEVELT ALVES DA SILVA
Externa à Instituição - KATYANNA SALES BEZERRA
Presidente - 1352009 - UMBERTO LAINO FULCO