Crystal Structures of Cholesteryl Ester Transfer Protein in Complex with Inhibitors

Liu, Shenping; Mistry, Anil; Reynolds, Jennifer M.; Lloyd, David B.; Griffor, Matthew C.; Perry, David A.; Ruggeri, Roger B.; Clark, Ronald W.; Qiu, Xiayang

doi:10.1074/jbc.m112.380063

Cited by 65 publications

(64 citation statements)

References 44 publications

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“…Many of the members of the TULIP superfamily have been shown to bind lipids or other long hydrophobic ligands [47,[55][56][57][58][59][60][61][62][63][64]. A lipid-binding assay using lipid interaction strips was performed finding that OrfX1 and OrfX2 could indeed bind to several types of phosphatidylinositol-phosphate (PIP) lipids.…”

Section: Lipid Bindingmentioning

confidence: 99%

Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX‐type gene cluster

et al. 2017

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Botulinum neurotoxins are highly toxic substances and are all encoded together with one of two alternative gene clusters, the HA or the OrfX gene cluster. Very little is known about the function and structure of the proteins encoded in the OrfX gene cluster, which in addition to the toxin contains five proteins (OrfX1, OrfX2, OrfX3, P47, and NTNH). We here present the structures of OrfX2 and P47, solved to 2.1 and 1.8 Å, respectively. We show that they belong to the TULIP protein superfamily, which are often involved in lipid binding. OrfX1 and OrfX2 were both found to bind phosphatidylinositol lipids.

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Section: Lipid Bindingmentioning

confidence: 99%

Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX‐type gene cluster

et al. 2017

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“…Another possible explanation for the under‐prediction of anacetrapib's terminal half‐life by the PBPK approach is that binding to CETP in plasma and tissues is not accounted for in the current prediction. Although anacetrapib and evacetrapib have similar binding affinities for CETP, the location of binding within the enzyme differs and rates of dissociation may also differ …”

Section: Discussionmentioning

confidence: 99%

“…Although anacetrapib and evacetrapib have similar binding affinities for CETP, the location of binding within the enzyme differs and rates of dissociation may also differ. 21 This work had a number of potential limitations. As with most modeling exercises, both modeling approaches required assumptions about the model structures and parameters, but we believe that the assumptions were reasonable and consistent with known properties of the molecules.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the persistence of anacetrapib and evacetrapib concentrations using two pharmacokinetic modeling approaches

Small

Hall

et al. 2015

The Journal of Clinical Pharma

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Anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, has been reported to have longer elimination half-life after longer treatment. Two pharmacokinetic model-based approaches were used to assess whether evacetrapib, another CETP inhibitor, could behave similarly. Using population pharmacokinetic (PopPK) modeling, evacetrapib and anacetrapib pharmacokinetics were characterized using available concentration-time data, and steady-state conditions were simulated. Published 2-compartment models for each compound were adapted to include a hypothetical third compartment representing a depot into which drug could partition. Physiologically based pharmacokinetic (PBPK) modeling was used to predict steady-state conditions and terminal half-life based on known physicochemical and dispositional properties. The PopPK model described the anacetrapib data well, showing a likely third compartment with estimated apparent volume of 40,700 L. Anacetrapib's estimated half-life for this compartment was 550 days. Simulations for evacetrapib using a hypothetical 3-compartment model, the third compartment being consistent with that of the anacetrapib model, produced predictions inconsistent with reported results, indicating that evacetrapib did not substantially accumulate into a large compartment. The PBPK simulations were consistent with PopPK results, predicting accumulation for anacetrapib (but not evacetrapib) followed by very slow elimination. Based on available data and known physicochemical properties, evacetrapib is not expected to accumulate substantially during long-term treatment.

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“…The X‐ray crystal structure of CETP (PDB ID: 4EWS) was adopted from the RCSB Protein Data Bank. CETP structure was prepared and energetically minimized using the Protein Preparation panel in the Schrödinger software enterprise to maximize H‐bond interactions.…”

Section: Methodsmentioning

confidence: 99%

“…The synthesized compounds (ligands) were built based on the co‐crystallized ligand's (ORP) coordinates in 4EWS . The ligands were built using MAESTRO build wizard and energetically minimized by MacroModel program recruiting the OPLS2005 force field.…”

Section: Methodsmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Molecular Modeling Study of Substituted Benzyl Benzamides as CETP Inhibitors

Khalaf

Sabbah

Al‐Shalabi

et al. 2017

Archiv der Pharmazie

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Cardiovascular disease is the most common cause for mortality and morbidity in the developed world; its risk is inversely related to the high-density lipoprotein (HDL) cholesterol levels. Therefore, there is a great interest in developing new cholesteryl ester transfer protein (CETP) inhibitors capable of raising HDL as a novel approach for the prevention of cardiovascular disease. Herein, the synthesis and characterization of ten benzyl benzamides 8a-j that aim at CETP inhibition was performed. The in vitro CETP inhibition bioassay revealed that benzamide 8j had the best activity, with a percent inhibition of 82.2% at 10 μM concentration and an IC value of 1.3 μM. The docking study shows that the verified compounds accommodate the binding cleft of CETP and are enclosed by a hydrophobic lining. Furthermore, the scaffold of 8a-j matches the pharmacophoric points of CETP inhibitors, particularly in its hydrophobic and aromatic functionalities.

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Crystal Structures of Cholesteryl Ester Transfer Protein in Complex with Inhibitors

Cited by 65 publications

References 44 publications

Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX‐type gene cluster

Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX‐type gene cluster

Assessment of the persistence of anacetrapib and evacetrapib concentrations using two pharmacokinetic modeling approaches

Synthesis, Biological Evaluation, and Molecular Modeling Study of Substituted Benzyl Benzamides as CETP Inhibitors

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