Ensemble Docking Approach to Mitigate Pregnane X Receptor-Mediated CYP3A4 Induction Risk

Three structurally closely related dopamine D1 receptor positive allosteric modulators (D1 PAMs) based on a tetrahydroisoquinoline (THIQ) scaffold were profiled for their CYP3A4 induction potentials. It was found that the length of the linker at the C5 position greatly affected the potentials of the...

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Published inJournal of chemical information and modeling Vol. 63; no. 1; pp. 173 - 186
Main Authors Chen, Qi, Zhou, Xin, Rehmel, Jessica, Steele, James P., Svensson, Kjell A., Beck, James P., Hembre, Erik J., Hao, Junliang
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 09.01.2023
Subjects
Binding
Computational Chemistry
Cytochrome P-450 CYP3A - metabolism
Docking
Dopamine
Enzyme Induction
Homology
Modulators
Pregnane X Receptor - metabolism
Receptors
Receptors, Steroid - chemistry
Receptors, Steroid - genetics
Receptors, Steroid - metabolism
Scaffolds
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Abstract Three structurally closely related dopamine D1 receptor positive allosteric modulators (D1 PAMs) based on a tetrahydroisoquinoline (THIQ) scaffold were profiled for their CYP3A4 induction potentials. It was found that the length of the linker at the C5 position greatly affected the potentials of these D1 PAMs as CYP3A4 inducers, and the level of induction correlated well with the activation of the pregnane X receptor (PXR). Based on the published PXR X-ray crystal structures, we built a binding model specifically for these THIQ-scaffold-based D1 PAMs in the PXR ligand-binding pocket via an ensemble docking approach and found the model could explain the observed CYP induction disparity. Combined with our previously reported D1 receptor homology model, which identified the C5 position as pointing toward the solvent-exposed space, our PXR-binding model coincidentally suggested that structural modifications at the C5 position could productively modulate the CYP induction potential while maintaining the D1 PAM potency of these THIQ-based PAMs.
AbstractList Three structurally closely related dopamine D1 receptor positive allosteric modulators (D1 PAMs) based on a tetrahydroisoquinoline (THIQ) scaffold were profiled for their CYP3A4 induction potentials. It was found that the length of the linker at the C5 position greatly affected the potentials of these D1 PAMs as CYP3A4 inducers, and the level of induction correlated well with the activation of the pregnane X receptor (PXR). Based on the published PXR X-ray crystal structures, we built a binding model specifically for these THIQ-scaffold-based D1 PAMs in the PXR ligand-binding pocket via an ensemble docking approach and found the model could explain the observed CYP induction disparity. Combined with our previously reported D1 receptor homology model, which identified the C5 position as pointing toward the solvent-exposed space, our PXR-binding model coincidentally suggested that structural modifications at the C5 position could productively modulate the CYP induction potential while maintaining the D1 PAM potency of these THIQ-based PAMs.Three structurally closely related dopamine D1 receptor positive allosteric modulators (D1 PAMs) based on a tetrahydroisoquinoline (THIQ) scaffold were profiled for their CYP3A4 induction potentials. It was found that the length of the linker at the C5 position greatly affected the potentials of these D1 PAMs as CYP3A4 inducers, and the level of induction correlated well with the activation of the pregnane X receptor (PXR). Based on the published PXR X-ray crystal structures, we built a binding model specifically for these THIQ-scaffold-based D1 PAMs in the PXR ligand-binding pocket via an ensemble docking approach and found the model could explain the observed CYP induction disparity. Combined with our previously reported D1 receptor homology model, which identified the C5 position as pointing toward the solvent-exposed space, our PXR-binding model coincidentally suggested that structural modifications at the C5 position could productively modulate the CYP induction potential while maintaining the D1 PAM potency of these THIQ-based PAMs.
Three structurally closely related dopamine D1 receptor positive allosteric modulators (D1 PAMs) based on a tetrahydroisoquinoline (THIQ) scaffold were profiled for their CYP3A4 induction potentials. It was found that the length of the linker at the C5 position greatly affected the potentials of these D1 PAMs as CYP3A4 inducers, and the level of induction correlated well with the activation of the pregnane X receptor (PXR). Based on the published PXR X-ray crystal structures, we built a binding model specifically for these THIQ-scaffold-based D1 PAMs in the PXR ligand-binding pocket via an ensemble docking approach and found the model could explain the observed CYP induction disparity. Combined with our previously reported D1 receptor homology model, which identified the C5 position as pointing toward the solvent-exposed space, our PXR-binding model coincidentally suggested that structural modifications at the C5 position could productively modulate the CYP induction potential while maintaining the D1 PAM potency of these THIQ-based PAMs.
Author Steele, James P.
Hembre, Erik J.
Beck, James P.
Chen, Qi
Zhou, Xin
Svensson, Kjell A.
Hao, Junliang
Rehmel, Jessica
AuthorAffiliation Discovery Chemistry Research and Technologies, Lilly Research Laboratories
Discovery Chemistry Research and Technologies, Lilly Biotechnology Center
Drug Disposition, Lilly Biotechnology Center
Neuroscience Discovery, Lilly Research Laboratories
Quantitative Biology, Lilly Research Laboratories
Drug Disposition, Lilly Research Laboratories
Eli Lilly and Company
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Snippet Three structurally closely related dopamine D1 receptor positive allosteric modulators (D1 PAMs) based on a tetrahydroisoquinoline (THIQ) scaffold were...
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SubjectTerms Binding
Computational Chemistry
Cytochrome P-450 CYP3A - metabolism
Docking
Dopamine
Enzyme Induction
Homology
Modulators
Pregnane X Receptor - metabolism
Receptors
Receptors, Steroid - chemistry
Receptors, Steroid - genetics
Receptors, Steroid - metabolism
Scaffolds
Title Ensemble Docking Approach to Mitigate Pregnane X Receptor-Mediated CYP3A4 Induction Risk
URI http://dx.doi.org/10.1021/acs.jcim.2c01175
https://www.ncbi.nlm.nih.gov/pubmed/36473234
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