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 |
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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 |
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