Ligand-Based Design of a Potent and Selective Inhibitor of Cytochrome P450 2C19

Foti, R.; Rock, Dan A.; Han, Xiaogang; Flowers, Robert A.; Wienkers, Larry C.; Wahlstrom, Jan L.

doi:10.1021/jm201346g

Cited by 13 publications

(12 citation statements)

References 38 publications

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“…As shown in Figure 4 E,F, Val113, Phe114, Ile205, Ile366, and Phe476 were important for the interactions between sauchinone and CYP2C19. It has been reported that Val113, Phe114, Ile205, Ile366, and Phe476 are crucial residues for ligand binding in CYP2C19 [ 41 , 42 ]. Sauchinone exhibited the lowest binding energy of −1.81 kcal/mol at the active site of CYP2E1, consistent with its least inhibition against human CYP2E1 ( K i = 41.70 µM).…”

Section: Discussionmentioning

confidence: 99%

Enzyme Kinetics and Molecular Docking Studies on Cytochrome 2B6, 2C19, 2E1, and 3A4 Activities by Sauchinone

et al. 2018

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Sauchinone, an active lignan isolated from the aerial parts of Saururus chinensis (Saururaceae), exhibits anti-inflammatory, anti-obesity, anti-hyperglycemic, and anti-hepatic steatosis effects. As herb–drug interaction (HDI) through cytochrome P450s (CYPs)-mediated metabolism limits clinical application of herbs and drugs in combination, this study sought to explore the enzyme kinetics of sauchinone towards CYP inhibition in in vitro human liver microsomes (HLMs) and in vivo mice studies and computational molecular docking analysis. In in vitro HLMs, sauchinone reversibly inhibited CYP2B6, 2C19, 2E1, and 3A4 activities in non-competitive modes, showing inhibition constant (Ki) values of 14.3, 16.8, 41.7, and 6.84 μM, respectively. Also, sauchinone time-dependently inhibited CYP2B6, 2E1 and 3A4 activities in vitro HLMs. Molecular docking study showed that sauchinone could be bound to a few key amino acid residues in the active site of CYP2B6, 2C19, 2E1, and 3A4. When sibutramine, clopidogrel, or chlorzoxazone was co-administered with sauchinone to mice, the systemic exposure of each drug was increased compared to that without sauchinone, because sauchinone reduced the metabolic clearance of each drug. In conclusion, when sauchinone was co-treated with drugs metabolized via CYP2B6, 2C19, 2E1, or 3A4, sauchinone–drug interactions occurred because sauchinone inhibited the CYP-mediated metabolic activities.

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Section: Discussionmentioning

confidence: 99%

Enzyme Kinetics and Molecular Docking Studies on Cytochrome 2B6, 2C19, 2E1, and 3A4 Activities by Sauchinone

et al. 2018

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“…The individual CYP isoforms come in different shapes, sizes, and compositions, contributing to unique substrate specificity profiles. The key structural features of a few important CYP inhibitors have been elucidated using X-ray crystallography, pharmacophore modeling, and various other in silico approaches [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. In particular, the structural features of CYP3A4 inhibitors have been well studied [ 30 , 39 , 40 , 41 , 42 , 43 ]; however, data on the specific structural features of inhibitors for the other four major cytochromes are limited and warrant further investigation.…”

Section: Structural Propertiesmentioning

confidence: 99%

Descriptors of Cytochrome Inhibitors and Useful Machine Learning Based Methods for the Design of Safer Drugs

Beck

Morningstar

et al. 2021

Pharmaceuticals

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Roughly 2.8% of annual hospitalizations are a result of adverse drug interactions in the United States, representing more than 245,000 hospitalizations. Drug–drug interactions commonly arise from major cytochrome P450 (CYP) inhibition. Various approaches are routinely employed in order to reduce the incidence of adverse interactions, such as altering drug dosing schemes and/or minimizing the number of drugs prescribed; however, often, a reduction in the number of medications cannot be achieved without impacting therapeutic outcomes. Nearly 80% of drugs fail in development due to pharmacokinetic issues, outlining the importance of examining cytochrome interactions during preclinical drug design. In this review, we examined the physiochemical and structural properties of small molecule inhibitors of CYPs 3A4, 2D6, 2C19, 2C9, and 1A2. Although CYP inhibitors tend to have distinct physiochemical properties and structural features, these descriptors alone are insufficient to predict major cytochrome inhibition probability and affinity. Machine learning based in silico approaches may be employed as a more robust and accurate way of predicting CYP inhibition. These various approaches are highlighted in the review.

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“…This can provide new avenues to find novel orthosteric/allosteric chemotypes , of GPR88 by using structure-based drug design (SBDD), such as a virtual screening strategy . Fragment-based drug design (FBDD) − and ligand-based drug design ,, may also each provide efficient strategies to identify more effective and selective GPR88 agonists and also antagonists with improved druglikeness by taking advantage of privileged fragments and newly identified synthetic ligands. Moreover, it is of great value for structural biologists to resolve the GPR88 structure and GPR88 receptor–ligand complexes using biophysical methods to pave the way for mechanistic studies and rational drug design.…”

Section: Conclusion and Future Directionsmentioning

confidence: 99%

Orphan Receptor GPR88 as an Emerging Neurotherapeutic Target

Mao

et al. 2018

ACS Chem. Neurosci.

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Although G protein-coupled receptors (GPCRs) are recognized as pivotal drug targets involved in multiple physiological and pathological processes, the majority of GPCRs including orphan GPCRs (oGPCRs) are unexploited. GPR88, a brain-specific oGPCR with particularly robust expression in the striatum, regulates diverse brain and behavioral functions, including cognition, mood, movement control, and reward-based learning, and is thus emerging as a novel drug target for central nervous system disorders including schizophrenia, Parkinson’s disease, anxiety, and addiction. Nevertheless, no effective GPR88 synthetic ligands have yet entered into clinical trials, and GPR88 endogenous ligands remain unknown. Despite the recent discovery and early stage study of several GPR88 agonists, such as 2-PCCA, RTI-13951–33, and phenylglycinol derivatives, further research into GPR88 pharmacology, medicinal chemistry, and chemical biology is urgently needed to yield structurally diversified GPR88-specific ligands. Drug-like pharmacological tool function and relevant signaling elucidation will also accelerate the evaluation of this receptor as a viable neurotherapeutic target.

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Ligand-Based Design of a Potent and Selective Inhibitor of Cytochrome P450 2C19

Cited by 13 publications

References 38 publications

Enzyme Kinetics and Molecular Docking Studies on Cytochrome 2B6, 2C19, 2E1, and 3A4 Activities by Sauchinone

Enzyme Kinetics and Molecular Docking Studies on Cytochrome 2B6, 2C19, 2E1, and 3A4 Activities by Sauchinone

Descriptors of Cytochrome Inhibitors and Useful Machine Learning Based Methods for the Design of Safer Drugs

Orphan Receptor GPR88 as an Emerging Neurotherapeutic Target

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