Molecular Mechanisms of Pharmaceutical Drug Binding into Calsequestrin

Autor: Kevin M. Lewis, Emiliano J. Sanchez, Hendrik Milting, Arun K Subra, ChulHee Kang, Ashwin K Muralidharan, Mark S. Nissen
Rok vydání: 2012
Předmět:
Protein Conformation
skeletal calsequestrin
Plasma protein binding
PFN
Ligands
Calsequestrin
lcsh:Chemistry
TFP
Non-competitive inhibition
Protein structure
thioridazine
calsequestrin
propafenone
DSP
lcsh:QH301-705.5
Spectroscopy
0303 health sciences
Molecular Structure
trifluoperazine
Chemistry
030302 biochemistry & molecular biology
General Medicine
SR
isothermal titration calorimetry
3. Good health
Computer Science Applications
Molecular Docking Simulation
CASQ2
Dissociation constant
CASQ1
Pharmaceutical Preparations
CASQ
sarcoplasmic reticulum
cardiac calsequestrin
ITC
daunomycin
DAN
desipramine
diltiazem
DTZ
TDZ
Rabbits
Protein Binding
Stereochemistry
Molecular Dynamics Simulation
Binding
Competitive

Article
Catalysis
Inorganic Chemistry
03 medical and health sciences
Animals
Protein Interaction Domains and Motifs
Amino Acid Sequence
Physical and Theoretical Chemistry
Binding site
Molecular Biology
030304 developmental biology
Binding Sites
Organic Chemistry
Isothermal titration calorimetry
Kinetics
lcsh:Biology (General)
lcsh:QD1-999
Docking (molecular)
Quantum Theory
Protein Multimerization
Zdroj: International Journal of Molecular Sciences, Vol 13, Iss 11, Pp 14326-14343 (2012)
International Journal of Molecular Sciences
International Journal of Molecular Sciences; Volume 13; Issue 11; Pages: 14326-14343
ISSN: 1422-0067
DOI: 10.3390/ijms131114326
Popis: Calsequestrin (CASQ) is a major Ca2+-storage/buffer protein present in the sarcoplasmic reticulum of both skeletal (CASQ1) and cardiac (CASQ2) muscles. CASQ has significant affinity for a number of pharmaceutical drugs with known muscular toxicities. Our approach, with in silico molecular docking, single crystal X-ray diffraction, and isothermal titration calorimetry (ITC), identified three distinct binding pockets on the surface of CASQ2, which overlap with 2-methyl-2,4-pentanediol (MPD) binding sites observed in the crystal structure. Those three receptor sites based on canine CASQ1 crystal structure gave a high correlation (R2 = 0.80) to our ITC data. Daunomycin, doxorubicin, thioridazine, and trifluoperazine showed strong affinity to the S1 site, which is a central cavity formed between three domains of CASQ2. Some of the moderate-affinity drugs and some high-affinity drugs like amlodipine and verapamil displayed their binding into S2 sites, which are the thioredoxin-like fold present in each CASQ domain. Docking predictions combined with dissociation constants imply that presence of large aromatic cores and less flexible functional groups determines the strength of binding affinity to CASQ. In addition, the predicted binding pockets for both caffeine and epigallocatechin overlapped with the S1 and S2 sites, suggesting competitive inhibition by these natural compounds as a plausible explanation for their antagonistic effects on cardiotoxic side effects.
Databáze: OpenAIRE