Banca de DEFESA: SARAH HESSING LOUZADA

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : SARAH HESSING LOUZADA
DATE: 09/09/2025
TIME: 14:30
LOCAL: PQ - sala 12
TITLE:

Identification of Allosteric Ligands of Dengue Virus Polymerase Using SBDD and FBDD Strategies

KEY WORDS:

Dengue; Polymerase; NS5; Virtual Screening; FBDD

PAGES: 140
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SPECIALTY: Estrutura, Conformação e Estereoquímica
SUMMARY:

Dengue is an arbovirus endemic to tropical and subtropical regions. The incidence of dengue has increased in recent decades, particularly due to climate change. This represents a serious public health problem, exacerbated by the lack of licensed antivirals. Nonstructural protein 5 (NS5), which acts as an RNA-dependent RNA polymerase (RdRp), is essential for viral replication. It is highly conserved across serotypes and has no homologues in humans, making it a strategic target for drug development. In this study, we applied a virtual screening approach based on structure docking to identify ligands for the allosteric N site of NS5. A novel, non-commercial chemical library consisting of 657 compounds derived from dissertations and theses from the Graduate Program in Chemistry at UFRRJ was used. The screening was conducted with the GOLD 2023.2.0 program, ChemPLP scoring function, using the ensemble docking technique. The scores obtained were normalized by molecular mass and surface area to select fragments (mass <300 Da) and by √N (number of non-hydrogen atoms) to reduce bias related to molecular size. Twenty-three compounds were selected, 17 fragments and 5 larger molecules. Cinnamic acid, the best fragment in the mass criterion, was optimized by fragment growth techniques, generating the ligand (E)-3-(3-(2-carboxyvinyl)phenoxy)benzoic acid as the most promising derivative. The larger compounds stood out for establishing relevant interactions with key residues of the site, such as Arg729, Thr794, Trp795, and His800, including hydrogen bonds and cation–π interactions. Interaction enthalpies were estimated using the semiempirical PM7 method (MOPAC2016), considering implicit solvent, revealing very interesting values, up to -96 kcal/mol for (E)-3-(3-(2-carboxyvinyl)phenoxy)benzoic acid, which exceeds the value of the reference inhibitors. Among the larger compounds, two fully comply with Lipinski's rules, suggesting potential for oral administration and predicted toxicity comparable to or better than that of known inhibitors. In this context, the PPGQ2000701 series stands out. Fragment optimization also led to an improvement in the pharmacokinetic profile, eliminating the predicted interaction with CYPs. The results indicate that compounds from the PPGQ-UFRRJ library are promising candidates for DENV NS5 inhibitors and promising starting structures for rational drug design. Furthermore, FBDD techniques proved effective in improving the interaction and pharmacokinetic profiles of the ligands.

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