Banca de DEFESA: DANIEL MELO DE OLIVEIRA CAMPOS

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : DANIEL MELO DE OLIVEIRA CAMPOS
DATE: 17/03/2020
TIME: 08:00
LOCAL: Sala II - DBF
TITLE:

Energetic Analysis of Intermolecular Interactions of peptidomimetic boronic acidic (cn-716) and aldehyde (Acyl-KR-Aldehyde) Inhibitors with Zika Virus NS2B-NS3 Protease

KEY WORDS:

Zika virus. NS2B-NS3 protease. cn-716. Acyl-KR-Aldehyde. DFT. MFCC.

PAGES: 75
BIG AREA: Ciências Biológicas
AREA: Biofísica
SUMMARY:

The reemergent Zika virus (ZIKV) infection has become a threat to global health due to the association with severe neurological abnormalities, namely Guillain-Barre Syndrome (GBS) in adults and Congenital Zika virus Syndrome (CZS) in neonates. Many studies are being conducted to find an effective antiviral drug against ZIKV. NS2B-NS3 protease is an attractive drug target due to essential function in viral replication, but to date, there are no commercially available. In this context, to will contribute in rational drug design for the development of an efficient anti-ZIKV, we conduct a comparative structural study based on quantum mechanical calculations to analyses the intermolecular binding energies between the crystallographic structure of NS2B-NS3 protease with dipeptides boronic acid (cn-716) and aldehyde (Acyl-KR-Aldehyde) peptidomimetic inhibitors. For this, we used the molecular fractionation with conjugate caps (MFCC) scheme within the density functional theory (DFT) formalism to describe in detail the energies of the complex. Our results reveal that the aldehyde inhibitor was shown to have more affinity than the boronic acid inhibitor. The Asp83 residue presents the most interaction energy in both inhibitors, binding with P2-residue, while Asp129 those that better interact with P1-residue. In general, the P2 residue of aldehyde inhibitor presents more affinity with the active site of protease than boronic acid inhibitor due to the presence of two phenolic rings that increasing the distance and decreasing the interaction. In addition, we highlight the amino acids residues Asp83*, His51, Asp129, Ser81*, Gly133, Ala132, Tyr161, Asn152 and Asp75 (Asp83*, Asp129 His51, Asn152, Tyr161, Tyr130, Gly153, Gly151, Asp75, Pro131, and Gly82) em cn-716/NS2B-NS3 (Acil-KR-Aldeído/NS2B-NS3). The amino acid Asn152 proved to be a key residue, influencing other amino acids neighboring the binding pocket to interact with greater affinity with the inhibitor. Additionally, we made missense mutation analyzes of these residues that compound to evaluate the destabilization and increase of flexibilization on protease, showing that mutation of Tyr161 followed by Tyr130 causes more impact on protease. Our simulations are valuable for a better understanding of the binding mechanism of recognized inhibitors of the NS2B-NS3 protease and can lead to the rational design and the development of novel IBU-derived drugs with improved potency.

BANKING MEMBERS:
Presidente - 2985070 - JONAS IVAN NOBRE OLIVEIRA
Externo ao Programa - 1715230 - JOSELIO MARIA GALVAO DE ARAUJO
Externo à Instituição - CLAUDIO BRUNO SILVA DE OLIVEIRA - F.M.Nassau