Banca de DEFESA: GABRIELA DE LIMA MENEZES

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
STUDENT : GABRIELA DE LIMA MENEZES
DATE: 12/12/2025
TIME: 09:00
LOCAL: Google Meet
TITLE:

Molecular and quantum analysis of the binding modes and affinities of melatonin, agomelatine, and their analogues with MT1 and MT2 receptors

KEY WORDS:

Computational biology, density functional theory, depression, rational drug design, quantum computations

PAGES: 97
BIG AREA: Ciências Biológicas
AREA: Biologia Geral
SUMMARY:

Sleep disorders and depression stand out among the conditions that most impact the global population, resulting in social and economic problems for those who suffer from them, which often occur simultaneously. Non-pharmacological treatments have limited efficacy, mainly due to low adherence and difficulty in continuity. Drug treatments, especially those with synthetic drugs, demonstrate greater efficacy; however, they present several side effects. Melatonin, in turn, demonstrates limited efficacy due to its short duration of action. This study aimed to evaluate, using computational tools, the molecular interaction between melatonin (mainly used in the treatment of sleep disorders), agomelatine (indicated for the treatment of depression), and their analogues with the melatonin receptors MT1 and MT2. To this end, several theoretical levels were used in the calculations: classical mechanics, quantum mechanics, and hybrid mechanics, through various methodologies: molecular docking, molecular dynamics (MD), and energy calculations of protein-ligand interaction. The results demonstrated the remarkable correlation between the methodology employed and the experimental data, resulting in the appropriate arrangement of the molecules' affinity in relation to the receptors. Thus, it was possible to recognize common key residues in the interactions with the molecules, seven in MT1 (Phe179, Met107, Gly108, Val111, Val191, Val159, and Ile112) and six in MT2 (Phe192, Val124, Gly121, Val204, Leu172, and Asn268). Furthermore, new conserved interactions were observed (Gly108/Gly121, Val111/Val124, and Val191/Val204), which suggest the function of these amino acids as essential in the recognition between ligands and receptors. Moreover, the relevance of MD in optimizing experimentally determined structures and in obtaining, through hybrid calculations, the minimum energy configuration for ab initio analysis was highlighted. Thus, through analyses resulting from the study of interactions of structures that were resolved, optimized, or modeled by molecular docking, it became feasible to propose a new ligand: MPI, whose performance proved promising, especially in its interaction with the MT2 receptor. Furthermore, the interaction of a new molecule (GW117), whose main application is as an antidepressant, was examined. However, initial results indicated affinity for melatonin receptors, and it may also act as an agonist for them. When compared to its analogue, agomelatine, the results indicate superior activity at the MT2 receptor and similar efficacy at the MT1 receptor, demonstrating sustained interactions with melatonin analogues. Therefore, there is strong evidence that GW117 performs better than the drug agomelatine in sleep disorders, and may become an important ally in the treatment of depressive cases that coexist with sleep cycle alterations. Thus, the theoretical-computational data presented here open an opportunity for the development of new drugs for the treatment of insomnia; however, in vitro and in vivo studies are necessary to validate the observations made here.

COMMITTEE MEMBERS:
Externo ao Programa - 1216466 - JOHN FONTENELE ARAUJO - nullInterno - 2985070 - JONAS IVAN NOBRE OLIVEIRA
Externa à Instituição - KATYANNA SALES BEZERRA - UNICAMP
Externo à Instituição - ROOSEVELT ALVES DA SILVA
Presidente - 1352009 - UMBERTO LAINO FULCO