Banca de DEFESA: NATHALLY LIMA DO NASCIMENTO

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : NATHALLY LIMA DO NASCIMENTO
DATE: 27/06/2022
TIME: 13:00
LOCAL: https://conferenciaweb.rnp.br/webconf/carlos-mauricio-rabello-de-santanna
TITLE:

PLANNING BY MOLECULAR MODELING OF CANDIDATES FOR DUAL INHIBITORS OF PHOSPHOLIPASES A2 AND METALLOPROTEASES OF SNAKE VENOM

KEY WORDS:

snakebites, antivenom action, dual inhibitors, metalloprotease, phospholipase A2, semi-empirical method

PAGES: 97
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SPECIALTY: Estrutura, Conformação e Estereoquímica
SUMMARY:

The search for drugs with antivenom action can significantly contribute to the treatment of victims of snakebites. Given the complexity of the mechanism of toxic action of snake venoms, enzymatic inhibitors with multi-target action seem to be the most promising for this purpose. Molecular modeling is a tool that can help in the design of new drugs with this profile. Thus, this work aimed to design, through molecular modeling methods, compounds that are candidates for dual inhibitors of two of the main types of enzymes present in Brazilian snake venoms, metalloproteases (MP) and phospholipases A2 (PLA2). In a first step, molecular docking and semi-empirical molecular orbital methods were applied to the study of structural and energetic aspects of human PLA2 inhibition by indole compounds with known inhibitory activity. This previous study allowed us to identify important pharmacophoric elements for the interaction of the compounds with PLA2. Study with the crystallographic structure of PLA2 from Bothrops jararacussu indicated that the conformation was not appropriate to study the interaction. Thus, a model of B. jararacussu PLA2 was constructed using human PLA2 as a template. The model had a more open conformation in the active site, which proved to be adequate to interact with the ligands in the following studies. As the objective is the development of dual action ligands, a study with a model of B. pauloensis MP, previously developed by our group and used in the design of effective inhibitors of snake venom MP, was implemented. Having information on the interactions of the two enzymes, pharmacophoric models were proposed for their inhibitors, which were combined to propose a series of structural modifications in thiosemicarbazones that already showed inhibitory activity on a PM isolated from the venom of B. pauloensis. Molecular docking and semi-empirical molecular orbital methods were used to study the interaction of these compounds with snake MP and PLA2 binding sites in order to evaluate the effects of proposed changes in the interaction with both, including structural and energetic information. All the designed compounds showed favorable interaction profiles with the two enzymes; the TmF-B ligand showed to be very promising, presenting a more favorable interaction enthalpy value in PLA2 than the reference PLA2 inhibitor (11S), as well as showing more favorable interaction energy in MP than the reference inhibitor (18). In a next step, the most promising compounds will be synthesized and evaluated experimentally to verify if there is indeed inhibition on snake MP and PLA2, which would characterize them as multi-target inhibitors with potential application in the treatment of snakebites.

BANKING MEMBERS:
Presidente - 1220404 - CARLOS MAURICIO RABELLO DE SANT ANNA
Interno - 1700480 - ARTHUR EUGEN KUMMERLE
Interna - 1979542 - RENATA BARBOSA LACERDA
Externa à Instituição - MAGALY GIRÃO ALBUQUERQUE - UFRJ
Externa à Instituição - NELILMA CORREIA ROMEIRO - UFRJ