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How anacetrapib inhibits the activity of the cholesteryl ester transfer protein? Perspective through atomistic simulations.

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  • معلومة اضافية
    • المصدر:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101238922 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7358 (Electronic) Linking ISSN: 1553734X NLM ISO Abbreviation: PLoS Comput Biol Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: San Francisco, CA : Public Library of Science, [2005]-
    • الموضوع:
      Cholesterol Ester Transfer Proteins/*antagonists & inhibitors ; Cholesterol Ester Transfer Proteins/*chemistry ; Oxazolidinones/*chemistry ; Oxazolidinones/*pharmacology; Cholesterol/chemistry ; Cholesterol/metabolism ; Cholesterol Ester Transfer Proteins/metabolism ; Humans ; Molecular Docking Simulation ; Phospholipids/chemistry ; Phospholipids/metabolism ; Static Electricity ; Thermodynamics
    • نبذة مختصرة :
      Cholesteryl ester transfer protein (CETP) mediates the reciprocal transfer of neutral lipids (cholesteryl esters, triglycerides) and phospholipids between different lipoprotein fractions in human blood plasma. A novel molecular agent known as anacetrapib has been shown to inhibit CETP activity and thereby raise high density lipoprotein (HDL)-cholesterol and decrease low density lipoprotein (LDL)-cholesterol, thus rendering CETP inhibition an attractive target to prevent and treat the development of various cardiovascular diseases. Our objective in this work is to use atomistic molecular dynamics simulations to shed light on the inhibitory mechanism of anacetrapib and unlock the interactions between the drug and CETP. The results show an evident affinity of anacetrapib towards the concave surface of CETP, and especially towards the region of the N-terminal tunnel opening. The primary binding site of anacetrapib turns out to reside in the tunnel inside CETP, near the residues surrounding the N-terminal opening. Free energy calculations show that when anacetrapib resides in this area, it hinders the ability of cholesteryl ester to diffuse out from CETP. The simulations further bring out the ability of anacetrapib to regulate the structure-function relationships of phospholipids and helix X, the latter representing the structural region of CETP important to the process of neutral lipid exchange with lipoproteins. Altogether, the simulations propose CETP inhibition to be realized when anacetrapib is transferred into the lipid binding pocket. The novel insight gained in this study has potential use in the development of new molecular agents capable of preventing the progression of cardiovascular diseases.
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    • الرقم المعرف:
      0 (CETP protein, human)
      0 (Cholesterol Ester Transfer Proteins)
      0 (Oxazolidinones)
      0 (Phospholipids)
      97C5T2UQ7J (Cholesterol)
      P7T269PR6S (anacetrapib)
    • الموضوع:
      Date Created: 20141121 Date Completed: 20151113 Latest Revision: 20190111
    • الموضوع:
      20221213
    • الرقم المعرف:
      PMC4238956
    • الرقم المعرف:
      10.1371/journal.pcbi.1003987
    • الرقم المعرف:
      25412509