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

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 bi...

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Published inInternational journal of molecular sciences Vol. 20; no. 4; p. 860
Main Authors Ramos, Joao, Muthukumaran, Jayaraman, Freire, Filipe, Paquete-Ferreira, João, Otrelo-Cardoso, Ana Rita, Svergun, Dmitri, Panjkovich, Alejandro, Santos-Silva, Teresa
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 16.02.2019
MDPI
Subjects
Apoptosis
Apoptosis - genetics
Binding Sites
Biophysical Phenomena
Bridged Bicyclo Compounds, Heterocyclic - chemistry
Cancer
Computer Simulation
Cytochrome
Homeostasis
Humans
Kinases
Ligands
Lymphoma
Mitochondria
Molecular Docking Simulation
Molecular Dynamics Simulation
NMR
Nuclear magnetic resonance
Physiology
Polymorphism, Single Nucleotide - genetics
Protein Binding
Protein Conformation
Proteins
Proto-Oncogene Proteins c-bcl-2 - chemistry
Proto-Oncogene Proteins c-bcl-2 - genetics
Sulfonamides - chemistry
Bcl-2
protein-ligand interactions
biophysical methods
bioinformatics
high throughput virtual screening
cell apoptosis
in silico
venetoclax
BH3 mimetics
Online AccessGet full text
ISSN1422-0067
1661-6596
1422-0067
DOI10.3390/ijms20040860

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Abstract 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.
AbstractList 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.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.
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.
Chromosomal translocation as a mechanism of Bcl-2 gene activation is associated with non-Hodgkin’s lymphomas, while the loss of endogenous miRNA and gene hypomethylation were reported in chronic lymphocytic leukemia (CLL) [12,13]. [...]Bcl-2 overexpression is correlated not only with non-Hodgkin’s lymphomas and CLL, but also small cell lung and breast cancers [14,15]. The binding groove plays a crucial role in the anti-apoptotic activity of bcl-2, as it accommodates the BH3 domain of the pro-apoptotic partners (Bax/Bak) [20]. [...]while Bcl-2 poses as a potential pharmacological target for inhibition, BH3 mimetics are the main category of promising therapeutic agents explored so far [8,21,22,23]. In the present work, we explore the human Bcl-2 protein-ligand interactions using biophysical and computational methods; experimental assays were carried out using a chimeric form of Bcl-2 where the FLD was replaced by a derivative loop from Bcl-xL to overcome protein precipitation, as described by Petros et al., while computational studies were carried out using chimeric and physiological forms, for comparison. In native conditions (i.e., in its final purification buffer) and in the presence of 2% DMSO, our Bcl-2 chimeric construct shows a melting temperature (Tm) of approximately 65 °C. Meanwhile, upon incubation with venetoclax, this value increases to 83 °C. A significant shift in the protein’s Tm of 18 °C is observed in the presence of the ligand (Figure 1).
Author Svergun, Dmitri
Muthukumaran, Jayaraman
Freire, Filipe
Paquete-Ferreira, João
Otrelo-Cardoso, Ana Rita
Ramos, Joao
Santos-Silva, Teresa
Panjkovich, Alejandro
AuthorAffiliation 1 UCIBIO-NOVA, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal; jc.ramos@campus.fct.unl.pt (J.R.); muthu@fct.unl.pt (J.M.); f.freire@campus.fct.unl.pt (F.F.); jcp.ferreira@campus.fct.unl.pt (J.P.-F.); a.cardoso@campus.fct.unl.pt (A.R.O.-C.)
2 European Molecular Biology Laboratory (EMBL), Hamburg Outstation, c/o DESY, 22067 Hamburg, Germany; svergun@embl-hamburg.de (D.S.); alejandro.panjkovich@embl-hamburg.de (A.P.)
AuthorAffiliation_xml – name: 2 European Molecular Biology Laboratory (EMBL), Hamburg Outstation, c/o DESY, 22067 Hamburg, Germany; svergun@embl-hamburg.de (D.S.); alejandro.panjkovich@embl-hamburg.de (A.P.)
– name: 1 UCIBIO-NOVA, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal; jc.ramos@campus.fct.unl.pt (J.R.); muthu@fct.unl.pt (J.M.); f.freire@campus.fct.unl.pt (F.F.); jcp.ferreira@campus.fct.unl.pt (J.P.-F.); a.cardoso@campus.fct.unl.pt (A.R.O.-C.)
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Issue 4
Keywords Bcl-2
protein-ligand interactions
biophysical methods
bioinformatics
high throughput virtual screening
cell apoptosis
in silico
venetoclax
BH3 mimetics
Language English
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These authors contributed equally to this work.
Institute Laue-Langevin, 71 avenue des Martyrs, CS 20136, 38042 Grenoble Cedex 9, France.
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901 Oeiras, Portugal.
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Snippet 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...
Chromosomal translocation as a mechanism of Bcl-2 gene activation is associated with non-Hodgkin’s lymphomas, while the loss of endogenous miRNA and gene...
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StartPage 860
SubjectTerms Apoptosis
Apoptosis - genetics
Binding Sites
Biophysical Phenomena
Bridged Bicyclo Compounds, Heterocyclic - chemistry
Cancer
Computer Simulation
Cytochrome
Homeostasis
Humans
Kinases
Ligands
Lymphoma
Mitochondria
Molecular Docking Simulation
Molecular Dynamics Simulation
NMR
Nuclear magnetic resonance
Physiology
Polymorphism, Single Nucleotide - genetics
Protein Binding
Protein Conformation
Proteins
Proto-Oncogene Proteins c-bcl-2 - chemistry
Proto-Oncogene Proteins c-bcl-2 - genetics
Sulfonamides - chemistry
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Title Shedding Light on the Interaction of Human Anti-Apoptotic Bcl-2 Protein with Ligands through Biophysical and in Silico Studies
URI https://www.ncbi.nlm.nih.gov/pubmed/30781512
https://www.proquest.com/docview/2332039389
https://www.proquest.com/docview/2184136713
https://pubmed.ncbi.nlm.nih.gov/PMC6413030
Volume 20
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