Banca de QUALIFICAÇÃO: MABELLE DE ARAUJO MEDEIROS

Uma banca de QUALIFICAÇÃO de MESTRADO foi cadastrada pelo programa.
STUDENT : MABELLE DE ARAUJO MEDEIROS
DATE: 29/10/2026
TIME: 09:00
LOCAL: Videoconferência
TITLE:

In silico evaluation of orientin as an inhibitor of the endonuclease enzyme from influenza in its wild and mutated state

KEY WORDS:

Orientin; Influenza; Endonuclease PA-Nter; I38T mutation; MFCC; Density Functionals Theory (DFT)

PAGES: 70
BIG AREA: Ciências Biológicas
AREA: Bioquímica
SUMMARY:

Influenza epidemics and pandemics pose serious global public health challenges, as seen in the 2009 H1N1 pandemic. Baloxavir marboxil (BXM) is an inhibitor of the endonuclease domain of the viral polymerase PA subunit (PA-Nter) and is the only approved influenza drug targeting this viral component. However, its efficacy is severely compromised by the I38T mutation, which is associated with the 2009 pandemic strain. Seeking a therapeutic alternative, this study aims to evaluate the activity and interaction profile of the flavonoid orientin (ORT) with both the wild-type and I38T-mutated endonucleases, derived from PDB codes 7NUG and 7NUH, respectively. The structures were optimized and subsequently subjected to energy minimization using the CHARMm force field. Interaction energies were calculated using Density Functional Theory (DFT) formalism, employing the B97D functional and the 6-311+G(d,p) basis set. The DFT approach was combined with the Molecular Fractionation with Conjugated Caps (MFCC) method under two dielectric constants (ε=10 and ε=40). Energy convergence analysis indicated that the medium with higher electrostatic shielding (ε=40) facilitated faster stabilization of both systems, as it is a better representative of the physiological aqueous environment. Orientin demonstrated a higher overall energetic affinity for the mutated ORT-I38T complex (-46.31 kcal/mol at ε=40) than for the wild-type ORT-Wild complex (-41.99 kcal/mol at ε=40). In the wild-type complex, notable attractive interactions involved LYS34 (-17.99 kcal/mol), ASP108 (-7.32 kcal/mol), and ILE38 (-4.57 kcal/mol), counterbalanced by the strong repulsion of GLU26 (11.26 kcal/mol). In the mutated variant, the primary attractive anchors were LYS34 (-13.96 kcal/mol), ASP108 (-6.11 kcal/mol), and the mutated residue THR38 itself (-6.06 kcal/mol), whose attraction exceeded that of ILE38 in the ORT-Wild complex. Furthermore, the mutated complex exhibited an attenuation of GLU26 repulsion (5.77 kcal/mol) and a shift in the catalytic residue GLU119 from repulsive to attractive (-2.31 kcal/mol). It is concluded that orientin preserves and enhances its binding affinity in the presence of the I38T mutation, establishing itself as a promising drug candidate to overcome antiviral resistance to baloxavir marboxil.

COMMITTEE MEMBERS:
Presidente - 2412258 - EDILSON DANTAS DA SILVA JUNIOR
Externa ao Programa - 3524072 - KATYANNA SALES BEZERRA - nullExterna à Instituição - ÉRIKA GEICIANNY DE CARVALHO MATIAS - SEEC