Banca de DEFESA: BRUNO HENRIQUE DE MEDEIROS MENDES

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : BRUNO HENRIQUE DE MEDEIROS MENDES
DATE: 22/12/2023
TIME: 09:00
LOCAL: https://conferenciaweb.rnp.br/webconf/carlos-mauricio-rabello-de-santanna
TITLE:

A new approach in the search for matrix metalloproteinase (MMP) inhibitors: studies on semicarbazones and thiosemicarbazones via molecular modeling

KEY WORDS:

Molecular Modeling, MMP9, Pharmacodynamics, Pharmacokinetics

PAGES: 256
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SPECIALTY: Estrutura, Conformação e Estereoquímica
SUMMARY:

Promising molecular targets for the search for new drugs for diseases such as dengue hemorrhagic fever, cancer, cardiovascular diseases and inflammation are matrix metalloproteases (MMPs), with emphasis on MMP-9, as it plays a central role in hemorrhagic and inflammatory processes and is frequently overexpressed in these pathologies. As there are different classes of MMPs, a central issue in the development of inhibitors of these enzymes is the search for selectivity. This project aims to analyze, using theoretical methods, the selectivity of semicarbazones (SC) and thiosemicarbazones (TSC), previously designed and synthesized by our group, in relation to MMP-9, aiming to design new candidates for selective inhibitors for this enzyme. Furthermore, the study seeks to analyze the pharmacokinetic properties of the most selective compounds using theoretical methods to determine their potential viability for human administration. Molecular docking studies were carried out with the structures of MMP-9 (PDB 6ESM) and MMP-1 (PDB 1HFC), with the Goldscore function. The complexes with the best poses were selected and subjected to geometric optimization via semi-empirical calculations with the PM7 method, adopting the protein in its entirety and in a continuous medium representing the solvent, to determine the interaction enthalpy of the compounds. The results show that ligands from the TSC group, in general, present a promising selectivity profile with human MMP-9, highlighting ligand 23b, which was used as the basis for a new series of more selective ligands. This approach resulted in relevant data on the interaction profile of TSC with the S1' sites of the MMP-1 and MMP-9 enzymes, explored in rational planning aiming at selectivity. The BH series ligands proved to be potentially selective, with emphasis on the BH02a molecule, which showed better interaction performance and selectivity for MMP-9 than 23b. The modifications were found to be beneficial for the predicted ADMET properties.The BH series balances solubility and membrane penetration, with improvements in TSC absorption, although BH02a and BH02b show slightly reduced absorption due to high polarity. Biodisponibility results indicate potential for oral drugs without PAINS alerts. With broad systemic distribution, especially the more lipophilic compounds in the BH series, they show potential for partitioning into lipid-rich regions such as the extracellular matrix. TSC inhibit CYP1A2, with BH01a also inhibiting CYP2C19, suggesting potential drug interactions, but proposed modifications reduced CYP3A4 inhibition. All compounds have low T1/2 and renal clearance, suggesting more frequent administration, and show no apparent cardiotoxicity. BH01a exhibits genotoxicity, and there is a general tendency toward hepatotoxicity, with 25, BH01, and BH01a being less hepatotoxic. TSC meet the FDA's maximum daily dose, indicating safe administration, and compounds 23b, 23c, 25, and the BH series have low acute toxicity, with BH01b, BH02, BH02a, and BH02b being the least toxic.

COMMITTEE MEMBERS:
Presidente - 1220404 - CARLOS MAURICIO RABELLO DE SANT ANNA
Interna - 1979542 - RENATA BARBOSA LACERDA
Externa à Instituição - MAGALY GIRÃO ALBUQUERQUE - UFRJ