Cargando…

Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach

BACKGROUND: Recent reports suggest the role of nonsynonymous single nucleotide polymorphisms (nsSNPs) in cyclin-dependent kinase 7 (CDK7) gene associated with defect in the DNA repair mechanism that may contribute to cancer risk. Among the various inhibitors developed so far, flavopiridol proved to...

Descripción completa

Detalles Bibliográficos
Autores principales: George Priya Doss, C, Nagasundaram, N, Chakraborty, Chiranjib, Chen, Luonan, Zhu, Hailong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726351/
https://www.ncbi.nlm.nih.gov/pubmed/23561625
http://dx.doi.org/10.1186/1479-7364-7-10
_version_ 1782278622773510144
author George Priya Doss, C
Nagasundaram, N
Chakraborty, Chiranjib
Chen, Luonan
Zhu, Hailong
author_facet George Priya Doss, C
Nagasundaram, N
Chakraborty, Chiranjib
Chen, Luonan
Zhu, Hailong
author_sort George Priya Doss, C
collection PubMed
description BACKGROUND: Recent reports suggest the role of nonsynonymous single nucleotide polymorphisms (nsSNPs) in cyclin-dependent kinase 7 (CDK7) gene associated with defect in the DNA repair mechanism that may contribute to cancer risk. Among the various inhibitors developed so far, flavopiridol proved to be a potential antitumor drug in the phase-III clinical trial for chronic lymphocytic leukemia. Here, we described a theoretical assessment for the discovery of new drugs or drug targets in CDK7 protein owing to the changes caused by deleterious nsSNPs. METHODS: Three nsSNPs (I63R, H135R, and T285M) were predicted to have functional impact on protein function by SIFT, PolyPhen2, I-Mutant3, PANTHER, SNPs&GO, PhD-SNP, and screening for non-acceptable polymorphisms (SNAP). Furthermore, we analyzed the native and proposed mutant models in atomic level 10 ns simulation using the molecular dynamics (MD) approach. Finally, with the aid of Autodock 4.0 and PatchDock, we analyzed the binding efficacy of flavopiridol with CDK7 protein with respect to the deleterious mutations. RESULTS: By comparing the results of all seven prediction tools, three nsSNPs (I63R, H135R, and T285M) were predicted to have functional impact on the protein function. The results of protein stability analysis inferred that I63R and H135R exhibited less deviation in root mean square deviation in comparison with the native and T285M protein. The flexibility of all the three mutant models of CDK7 protein is diverse in comparison with the native protein. Following to that, docking study revealed the change in the active site residues and decrease in the binding affinity of flavopiridol with mutant proteins. CONCLUSION: This theoretical approach is entirely based on computational methods, which has the ability to identify the disease-related SNPs in complex disorders by contrasting their costs and capabilities with those of the experimental methods. The identification of disease related SNPs by computational methods has the potential to create personalized tools for the diagnosis, prognosis, and treatment of diseases. LAY ABSTRACT: Cell cycle regulatory protein, CDK7, is linked with DNA repair mechanism which can contribute to cancer risk. The main aim of this study is to extrapolate the relationship between the nsSNPs and their effects in drug-binding capability. In this work, we propose a new methodology which (1) efficiently identified the deleterious nsSNPs that tend to have functional effect on protein function upon mutation by computational tools, (2) analyze d the native protein and proposed mutant models in atomic level using MD approach, and (3) investigated the protein-ligand interactions to analyze the binding ability by docking analysis. This theoretical approach is entirely based on computational methods, which has the ability to identify the disease-related SNPs in complex disorders by contrasting their costs and capabilities with those of the experimental methods. Overall, this approach has the potential to create personalized tools for the diagnosis, prognosis, and treatment of diseases.
format Online
Article
Text
id pubmed-3726351
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-37263512013-07-31 Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach George Priya Doss, C Nagasundaram, N Chakraborty, Chiranjib Chen, Luonan Zhu, Hailong Hum Genomics Primary Research BACKGROUND: Recent reports suggest the role of nonsynonymous single nucleotide polymorphisms (nsSNPs) in cyclin-dependent kinase 7 (CDK7) gene associated with defect in the DNA repair mechanism that may contribute to cancer risk. Among the various inhibitors developed so far, flavopiridol proved to be a potential antitumor drug in the phase-III clinical trial for chronic lymphocytic leukemia. Here, we described a theoretical assessment for the discovery of new drugs or drug targets in CDK7 protein owing to the changes caused by deleterious nsSNPs. METHODS: Three nsSNPs (I63R, H135R, and T285M) were predicted to have functional impact on protein function by SIFT, PolyPhen2, I-Mutant3, PANTHER, SNPs&GO, PhD-SNP, and screening for non-acceptable polymorphisms (SNAP). Furthermore, we analyzed the native and proposed mutant models in atomic level 10 ns simulation using the molecular dynamics (MD) approach. Finally, with the aid of Autodock 4.0 and PatchDock, we analyzed the binding efficacy of flavopiridol with CDK7 protein with respect to the deleterious mutations. RESULTS: By comparing the results of all seven prediction tools, three nsSNPs (I63R, H135R, and T285M) were predicted to have functional impact on the protein function. The results of protein stability analysis inferred that I63R and H135R exhibited less deviation in root mean square deviation in comparison with the native and T285M protein. The flexibility of all the three mutant models of CDK7 protein is diverse in comparison with the native protein. Following to that, docking study revealed the change in the active site residues and decrease in the binding affinity of flavopiridol with mutant proteins. CONCLUSION: This theoretical approach is entirely based on computational methods, which has the ability to identify the disease-related SNPs in complex disorders by contrasting their costs and capabilities with those of the experimental methods. The identification of disease related SNPs by computational methods has the potential to create personalized tools for the diagnosis, prognosis, and treatment of diseases. LAY ABSTRACT: Cell cycle regulatory protein, CDK7, is linked with DNA repair mechanism which can contribute to cancer risk. The main aim of this study is to extrapolate the relationship between the nsSNPs and their effects in drug-binding capability. In this work, we propose a new methodology which (1) efficiently identified the deleterious nsSNPs that tend to have functional effect on protein function upon mutation by computational tools, (2) analyze d the native protein and proposed mutant models in atomic level using MD approach, and (3) investigated the protein-ligand interactions to analyze the binding ability by docking analysis. This theoretical approach is entirely based on computational methods, which has the ability to identify the disease-related SNPs in complex disorders by contrasting their costs and capabilities with those of the experimental methods. Overall, this approach has the potential to create personalized tools for the diagnosis, prognosis, and treatment of diseases. BioMed Central 2013-04-05 /pmc/articles/PMC3726351/ /pubmed/23561625 http://dx.doi.org/10.1186/1479-7364-7-10 Text en Copyright © 2013 George Priya Doss et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Primary Research
George Priya Doss, C
Nagasundaram, N
Chakraborty, Chiranjib
Chen, Luonan
Zhu, Hailong
Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach
title Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach
title_full Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach
title_fullStr Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach
title_full_unstemmed Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach
title_short Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach
title_sort extrapolating the effect of deleterious nssnps in the binding adaptability of flavopiridol with cdk7 protein: a molecular dynamics approach
topic Primary Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726351/
https://www.ncbi.nlm.nih.gov/pubmed/23561625
http://dx.doi.org/10.1186/1479-7364-7-10
work_keys_str_mv AT georgepriyadossc extrapolatingtheeffectofdeleteriousnssnpsinthebindingadaptabilityofflavopiridolwithcdk7proteinamoleculardynamicsapproach
AT nagasundaramn extrapolatingtheeffectofdeleteriousnssnpsinthebindingadaptabilityofflavopiridolwithcdk7proteinamoleculardynamicsapproach
AT chakrabortychiranjib extrapolatingtheeffectofdeleteriousnssnpsinthebindingadaptabilityofflavopiridolwithcdk7proteinamoleculardynamicsapproach
AT chenluonan extrapolatingtheeffectofdeleteriousnssnpsinthebindingadaptabilityofflavopiridolwithcdk7proteinamoleculardynamicsapproach
AT zhuhailong extrapolatingtheeffectofdeleteriousnssnpsinthebindingadaptabilityofflavopiridolwithcdk7proteinamoleculardynamicsapproach