PMID- 23561625
OWN - NLM
STAT- MEDLINE
DCOM- 20131126
LR  - 20221207
IS  - 1479-7364 (Electronic)
IS  - 1473-9542 (Print)
IS  - 1473-9542 (Linking)
VI  - 7
IP  - 1
DP  - 2013 Apr 5
TI  - Extrapolating the effect of deleterious nsSNPs in the binding adaptability of 
      flavopiridol with CDK7 protein: a molecular dynamics approach.
PG  - 10
LID - 10.1186/1479-7364-7-10 [doi]
AB  - 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.
FAU - George Priya Doss, C
AU  - George Priya Doss C
AD  - Medical Biotechnology Division, Centre for Nanobiotechnology, School of 
      Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu 632014, 
      India. georgecp77@yahoo.co.in
FAU - Nagasundaram, N
AU  - Nagasundaram N
FAU - Chakraborty, Chiranjib
AU  - Chakraborty C
FAU - Chen, Luonan
AU  - Chen L
FAU - Zhu, Hailong
AU  - Zhu H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130405
PL  - England
TA  - Hum Genomics
JT  - Human genomics
JID - 101202210
RN  - 0 (Amino Acids)
RN  - 0 (Flavonoids)
RN  - 0 (Mutant Proteins)
RN  - 0 (Piperidines)
RN  - 45AD6X575G (alvocidib)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase-Activating Kinase)
RN  - 0 (CDK7 protein, human)
SB  - IM
MH  - Amino Acids/metabolism
MH  - Computer Simulation
MH  - Cyclin-Dependent Kinases/chemistry/*genetics/*metabolism
MH  - Flavonoids/chemistry/*metabolism
MH  - Humans
MH  - Hydrogen Bonding
MH  - *Molecular Dynamics Simulation
MH  - Mutant Proteins/chemistry/genetics
MH  - Piperidines/chemistry/*metabolism
MH  - Polymorphism, Single Nucleotide/*genetics
MH  - Protein Binding/genetics
MH  - Protein Structure, Secondary
MH  - Software
MH  - Static Electricity
MH  - Thermodynamics
MH  - Cyclin-Dependent Kinase-Activating Kinase
PMC - PMC3726351
EDAT- 2013/04/09 06:00
MHDA- 2013/12/16 06:00
PMCR- 2013/04/05
CRDT- 2013/04/09 06:00
PHST- 2013/02/03 00:00 [received]
PHST- 2013/02/18 00:00 [accepted]
PHST- 2013/04/09 06:00 [entrez]
PHST- 2013/04/09 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
PHST- 2013/04/05 00:00 [pmc-release]
AID - 1479-7364-7-10 [pii]
AID - 10.1186/1479-7364-7-10 [doi]
PST - epublish
SO  - Hum Genomics. 2013 Apr 5;7(1):10. doi: 10.1186/1479-7364-7-10.