Banca de DEFESA: CAIO PATRICIO DE SOUZA SENA

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
STUDENT : CAIO PATRICIO DE SOUZA SENA
DATE: 25/02/2026
TIME: 14:00
LOCAL: Videoconferência
TITLE:

Computational study of the structural and energetic bases governing the interaction between antagonists and orexin receptors.

KEY WORDS:

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

PAGES: 165
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Físico-Química
SPECIALTY: Química Teórica
SUMMARY:

The pharmacological class of orexin receptor antagonists (ORAs) represents an innovative approach for the treatment of insomnia, in contrast to classical modulators of the GABAA receptor, such as benzodiazepines and Z-drugs. By inhibiting the action of orexin, a neuropeptide that plays a fundamental role in the promotion and maintenance of wakefulness, ORAs facilitate sleep onset and maintenance and exhibit a pharmacological profile associated with a lower risk of abuse, dependence, and cognitive impairment when compared to traditional hypnotic therapies. A detailed understanding of the mechanisms governing ligand recognition and interaction with orexin receptors 1 and 2 (OXR1 and OXR2) is essential for the rational design of selective drugs aimed at the treatment of sleep disorders and neuropsychiatric conditions. In this work, a comprehensive computational investigation of the molecular interactions of three dual orexin receptor antagonists (DORAs), daridorexant, lemborexant, and suvorexant, as well as the OXR1-selective antagonist (1-SORA) nivasorexant and the OXR2-selective antagonist (2-SORA) seltorexant, was carried out. The integrated computational approach combined molecular docking studies, molecular dynamics (MD) simulations in an explicit membrane environment with a total simulation time exceeding 700 ns, and Density Functional Theory (DFT) calculations at the B97D/6-311+G(d,p) level for subsystems obtained using the Molecular Fractionation with Conjugate Caps (MFCC) methodology. Among the ligands investigated, daridorexant exhibited greater conformational adaptability and overall binding affinity, whereas lemborexant, suvorexant, seltorexant, and nivasorexant displayed receptor subtype-dependent stabilization patterns, with predominant contributions from hydrophobic and aromatic regions in OXR2 and OXR1. These profiles reflect differences in the topology, flexibility, and energetic landscape of the orthosteric binding sites of OXR1 and OXR2, in which complex stabilization is governed by specific contributions from key residues and by a characteristic balance among polar interactions, hydrogen bonds, and hydrophobic and aromatic contacts, with emphasis on GLU204, HIS216, and ASN318 in OXR1, particularly in the daridorexant complex, and on GLU212, GLN134, ILE320, PHE346, and HIS350 in OXR2, thereby elucidating, at the molecular level, the structural and energetic determinants of ligand–receptor interactions.

COMMITTEE MEMBERS:
Interno - 1086214 - ANDERSON DOS REIS ALBUQUERQUE
Presidente - 1959889 - DAVI SERRADELLA VIEIRA
Externo à Instituição - GUTTO RAFFYSON SILVA DE FREITAS - IFRN
Externo ao Programa - 2985070 - JONAS IVAN NOBRE OLIVEIRA - nullExterno à Instituição - MARCOS ROBERTO LOURENZONI - FIOCRUZ