Breaking the sensitivity limitations of cytochrome P450 oxidation product: Dansyl chloride derivatisation of 4-OH mephenytoin, a CYP2C19 metabolite and its application to in vitro CYP inhibition assay

2015 ◽  
Vol 989 ◽  
pp. 27-36 ◽  
Author(s):  
V. Vijayabhaskar ◽  
Pratima Srivastava ◽  
Sriram Rajagopal
Keyword(s):  
Cytochrome P450 ◽  
Oxidation Product ◽  
Dansyl Chloride ◽  
Inhibition Assay ◽  
Cyp Inhibition

Cytochrome P450 enzymes: a review on drug metabolizing enzyme inhibition studies in drug discovery and development

Bioanalysis ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 1355-1378
Author(s):  
Siva Nageswara Rao Gajula ◽  
Megha Sajakumar Pillai ◽  
Gananadhamu Samanthula ◽  
Rajesh Sonti
Keyword(s):  
Cytochrome P450 ◽  
Drug Discovery ◽  
Enzyme Inhibition ◽  
In Vitro Study ◽  
Cytochrome P450 Enzymes ◽  
Drug Discovery And Development ◽  
Drug Candidates ◽  
Cyp Enzymes ◽  
Cyp Inhibition

Assessment of drug candidate's potential to inhibit cytochrome P450 (CYP) enzymes remains crucial in pharmaceutical drug discovery and development. Both direct and time-dependent inhibition of drug metabolizing CYP enzymes by the concomitant administered drug is the leading cause of drug–drug interactions (DDIs), resulting in the increased toxicity of the victim drug. In this context, pharmaceutical companies have grown increasingly diligent in limiting CYP inhibition liabilities of drug candidates in the early stages and examining risk assessments throughout the drug development process. This review discusses different strategies and decision-making processes for assessing the drug–drug interaction risks by enzyme inhibition and lays particular emphasis on in vitro study designs and interpretation of CYP inhibition data in a stage-appropriate context.

Assessment of the in vitro cytochrome P450 (CYP) inhibition potential of nafithromycin, a next generation lactone ketolide antibiotic

Xenobiotica ◽  
2020 ◽  
pp. 1-11
Author(s):  
Rajesh Chavan ◽  
Vineet Zope ◽  
Nilesh Chavan ◽  
Kiran Patil ◽  
Ravindra Yeole ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Next Generation ◽  
Cyp Inhibition

Assessment of the in vitro cytochrome P450 (CYP) inhibition potential of ZYTP1, a novel poly (ADP-ribose) polymerase inhibitor

Xenobiotica ◽  
2019 ◽  
Vol 49 (10) ◽  
pp. 1164-1172
Author(s):  
Poonam Giri ◽  
Lakshmikant Gupta ◽  
Sanjay Singh ◽  
Nirmal Patel ◽  
Nuggehally R. Srinivas ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cyp Inhibition ◽  
Polymerase Inhibitor

scholarly journals Identification of Potential Lead Molecules against Dibenzo[a,l]pyrene-induced Mammary Cancer through Targeting Cytochrome P450 1A1, 1A2, and 1B1 Isozymes

2021 ◽  
Vol 12 (1) ◽  
pp. 1096-1109
Keyword(s):  
Cytochrome P450 ◽  
Mammary Cancer ◽  
Md Simulation ◽  
Inhibition Assay ◽  
Cytochrome P450 1A1 ◽  
Kcal Mole ◽  
Diphenyltetrazolium Bromide ◽  
Inhibitory Potential ◽  
Cyp Isozymes

Cytochrome P450 (CYP) isozymes are promising therapeutic targets against dibenzo[a,l]pyrene-induced mammary cancer. Current research aims to identify potential lead molecules against mammary cancer targetting CYP1A1, 1A2, and 1B1 using ligand-based virtual screening (LBVS), molecular interactions, MD simulation, and in vitro studies. The LBVS predicted 30,500 hits, which were reduced to 400 when sifted through Lipinski RO5, and ADMET parameters. These 400 compounds were carried forward for molecular docking with the selected CYP isozymes. The ligand CHEMBL224064 (CHEMBL1), CHEMBL2420083 (CHEMBL2), and CHEMBL61745 (CHEMBL3) depicted stronger binding respectively in CYP1A1 (-10-52 kcal/mol), 1A2 (-10.82 kcal/mol), and 1B1 (-10.78 kcal/mol) in comparison to known inhibitor alpha-naphthoflavone (ANF) (-9.13 kcal/mol, -9.66 kcal/mole, and -9.67 kcal/mol respectively in CYP1A1, 1A2, and 1B1). These compounds were found stable with their respective targets during MD studies of 50 ns duration. Furthermore, (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) (MTT) and enzyme inhibition assay elucidated and validated the inhibitory potential of identified ligands against mammary carcinomas. The study reveals a significant understanding of PAH-mediated mammary cancer and its prevention.

The Molecular and Enzyme Kinetic Basis for Altered Activity of Three Cytochrome P450 2C19 Variants Found in the Chinese Population

2020 ◽  
Vol 13 (3) ◽  
pp. 233-244
Author(s):  
Amelia Nathania Dong ◽  
Nafees Ahemad ◽  
Yan Pan ◽  
Uma Devi Palanisamy ◽  
Beow Chin Yiap ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Molecular Docking ◽  
Active Site ◽  
Chinese Population ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
In Vitro Assays ◽  
Access Channel ◽  
Cytochrome P450 2C19

Background: There is a large inter-individual variation in cytochrome P450 2C19 (CYP2C19) activity. The variability can be caused by the genetic polymorphism of CYP2C19 gene. This study aimed to investigate the molecular and kinetics basis for activity changes in three alleles including CYP2C19*23, CYP2C19*24 and CYP2C19*25found in the Chinese population. Methods: The three variants expressed by bacteria were investigated using substrate (omeprazole and 3- cyano-7-ethoxycoumarin[CEC]) and inhibitor (ketoconazole, fluoxetine, sertraline and loratadine) probes in enzyme assays along with molecular docking. Results: All alleles exhibited very low enzyme activity and affinity towards omeprazole and CEC (6.1% or less in intrinsic clearance). The inhibition studies with the four inhibitors, however, suggested that mutations in different variants have a tendency to cause enhanced binding (reduced IC50 values). The enhanced binding could partially be explained by the lower polar solvent accessible surface area of the inhibitors relative to the substrates. Molecular docking indicated that G91R, R335Q and F448L, the unique mutations in the alleles, have caused slight alteration in the substrate access channel morphology and a more compact active site cavity hence affecting ligand access and binding. It is likely that these structural alterations in CYP2C19 proteins have caused ligand-specific alteration in catalytic and inhibitory specificities as observed in the in vitro assays. Conclusion: This study indicates that CYP2C19 variant selectivity for ligands was not solely governed by mutation-induced modifications in the active site architecture, but the intrinsic properties of the probe compounds also played a vital role.

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