Banca de DEFESA: MONIQUE RODRIGUES DA COSTA

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : MONIQUE RODRIGUES DA COSTA
DATE: 09/12/2022
TIME: 14:00
LOCAL: https://meet.google.com/mnn-tcew-mrm
TITLE:

Use of molecular docking and similarity models employing substances with biological activity against PPARδ receptor

PAGES: 142
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Físico-Química
SPECIALTY: Química Teórica
SUMMARY:

Diabetes mellitus (DM) is a chronic disease characterized by a metabolic disorder arising from defects in insulin secretion and/or action, which results in hyperglycemia and causes a series of physiological complications. Considering that the disease has no cure and the existing treatments have side effects that compromise the quality of life of patients, it is necessary to search for more effective treatments. The PPAR (Peroxisome Proliferator-Activated Receptor) class of receptors controls the metabolic pathways of carbohydrates and lipids. A subclass of these receptors, the PPARδ subtype, regulates certain metabolic pathways so that substances that activate it can be used as drugs for type 2 DM (DMT2). In order to identify new drug candidates targeting the PPARδ receptor, a comprehensive study was performed by constructing and validating several chemical similarity models (MSQs) employing two different datasets, dataset 1, derived from substances synthesized by Wickens et al., and dataset 2, which was more diverse, i.e. composed of substances from different classes and different sources. These studies allowed us to understand which features were relevant for PPARδ activation, as well as showed that it is not possible to obtain a generic MSQ by employing the shape overlay method. At the end of this step, 2 MSQs were selected and showed enrichment and statistical parameter values, such as MCC, AUC, and FNR, related to good predictive ability of them. These models indicated the importance of hydrogen bonding acceptor groups located in the "head" of the molecule (groups responsible for interacting with key residues for receptor activation), corroborating data from the literature. Then, these models were applied in a virtual screening protocol in 4 different databases, allowing the identification of 3 new compounds (ZINC000047667300, ZINC0001123708171 and ZINC00004247309209) that present adequate pharmacokinetic properties according to in silico tools. Molecular docking studies showed that they perform important interactions for the PPARδ activation. However, the results are not yet conclusive and further in silico studies, such as molecular dynamics simulations, and biological assays are needed before these compounds can be indicated as possible drug candidates for the treatment of DMT2.

BANKING MEMBERS:
Presidente - Interno ao Programa - 149.405.258-05 - KATHIA MARIA HONORIO - USP
Membro Titular - Examinador(a) Interno ao Programa - 1766090 - MIRELA INES DE SAIRRE
Membro Titular - Examinador(a) Externo à Instituição - ALESSANDRO SILVA NASCIMENTO - USP
Membro Suplente - Examinador(a) Interno ao Programa - 1544394 - PAULA HOMEM DE MELLO
Membro Suplente - Examinador(a) Externo ao Programa - 1563992 - ANA LIGIA BARBOUR SCOTT