Shedding Light on the Interaction of Human Anti-Apoptotic Bcl-2 Protein with Ligands through Biophysical and in Silico Studies

Autor: Ana Rita Otrelo-Cardoso, Alejandro Panjkovich, João Paquete-Ferreira, Teresa Santos-Silva, Jayaraman Muthukumaran, Dmitri I. Svergun, Filipe Freire, Joao Ramos
Přispěvatelé: UCIBIO - Applied Molecular Biosciences Unit, DQ - Departamento de Química
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
BH3 mimetics
Protein Conformation
Apoptosis
Protein-ligand interactions
protein-ligand interactions
Ligands
lcsh:Chemistry
Molecular dynamics
chemistry.chemical_compound
Protein structure
lcsh:QH301-705.5
biophysical methods
Spectroscopy
Sulfonamides
Chemistry
General Medicine
bioinformatics
Computer Science Applications
Molecular Docking Simulation
Proto-Oncogene Proteins c-bcl-2
in silico
ddc:540
Protein Binding
030103 biophysics
Thermal shift assay
Bioinformatics
In silico
Single-nucleotide polymorphism
Molecular Dynamics Simulation
Polymorphism
Single Nucleotide

Biophysical Phenomena
Article
Catalysis
Venetoclax
Inorganic Chemistry
03 medical and health sciences
SDG 3 - Good Health and Well-being
Humans
Computer Simulation
Bcl-2
Physical and Theoretical Chemistry
Molecular Biology
Virtual screening
Biophysical methods
Binding Sites
cell apoptosis
venetoclax
High throughput virtual screening
Organic Chemistry
Bridged Bicyclo Compounds
Heterocyclic

030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
Biophysics
Cell apoptosis
high throughput virtual screening
Zdroj: International journal of molecular sciences 20(4), 860-(2019). doi:10.3390/ijms20040860
Repositório Científico de Acesso Aberto de Portugal
Repositório Científico de Acesso Aberto de Portugal (RCAAP)
instacron:RCAAP
International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 20, Iss 4, p 860 (2019)
Volume 20
Issue 4
DOI: 10.3204/pubdb-2019-03570
Popis: International journal of molecular sciences 20(4), 860 - (2019). doi:10.3390/ijms20040860
Bcl-2 protein is involved in cell apoptosis and is considered an interesting target for anti-cancer therapy. The present study aims to understand the stability and conformational changes of Bcl-2 upon interaction with the inhibitor venetoclax, and to explore other drug-target regions. We combined biophysical and in silico approaches to understand the mechanism of ligand binding to Bcl-2. Thermal shift assay (TSA) and urea electrophoresis showed a significant increase in protein stability upon venetoclax incubation, which is corroborated by molecular docking and molecular dynamics simulations. An 18 °C shift in Bcl-2 melting temperature was observed in the TSA, corresponding to a binding affinity multiple times higher than that of any other reported Bcl-2 inhibitor. This protein-ligand interaction does not implicate alternations in protein conformation, as suggested by SAXS. Additionally, bioinformatics approaches were used to identify deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) of Bcl-2 and their impact on venetoclax binding, suggesting that venetoclax interaction is generally favored against these deleterious nsSNPs. Apart from the BH3 binding groove of Bcl-2, the flexible loop domain (FLD) also plays an important role in regulating the apoptotic process. High-throughput virtual screening (HTVS) identified 5 putative FLD inhibitors from the Zinc database, showing nanomolar affinity toward the FLD of Bcl-2
Published by Molecular Diversity Preservation International, Basel
Databáze: OpenAIRE