Banca de QUALIFICAÇÃO: CAIO PATRICIO DE SOUZA SENA

Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.
STUDENT : CAIO PATRICIO DE SOUZA SENA
DATE: 15/12/2025
TIME: 08:00
LOCAL: Auditório - Química III
TITLE:

Computational study of the interaction mechanisms between antagonist drugs and orexin receptors.

KEY WORDS:

orexin receptors; DORAs; SORAs; molecular docking; molecular dynamics; DFT

PAGES: 120
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Físico-Química
SPECIALTY: Química Teórica
SUMMARY:

A detailed understanding of ligand recognition and binding mechanisms at orexin receptors 1 and 2 (OXR1 and OXR2) is essential for the rational design of selective therapeutics targeting sleep and neuropsychiatric disorders. In this thesis, a comprehensive computational investigation was conducted to elucidate the molecular interactions of three dual orexin receptor antagonists (DORAs) daridorexant, lemborexant, and suvorexant, alongside the OXR1-selective antagonist (1-SORA) nivaorexant and OXR2-selective antagonist (2-SORA) seltorexant. The integrated computational approach combined molecular docking studies, explicit-membrane molecular dynamics (MD) simulations extending over 700 ns, and density functional theory (DFT) calculations at the B97D/6-311+G(d,p) level for subsystems obtained through the molecular fractionation with conjugate caps (MFCC) methodology. Comparative analyses revealed distinct binding profiles between OXR1 and OXR2, reflecting differences in the topology, flexibility, and energetic landscape of their orthosteric binding sites. Among the investigated ligands, daridorexant exhibited the greatest adaptability and overall binding affinity, whereas seltorexant and nivaorexant displayed subtype-specific stabilization patterns within hydrophobic subpockets of OXR2 and OXR1, respectively. These findings provide molecular-level insights into the structural and energetic determinants governing orexin receptor–ligand interactions, establishing a solid theoretical framework for the rational optimization of orexin receptor antagonists with enhanced selectivity and pharmacological efficacy.

COMMITTEE MEMBERS:
Interno - 1086214 - ANDERSON DOS REIS ALBUQUERQUE
Presidente - 1959889 - DAVI SERRADELLA VIEIRA
Externo ao Programa - 2985070 - JONAS IVAN NOBRE OLIVEIRA - null