ELIZA

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296134 occurrences (No.80 in the rank) during 5 years in the PubMed. [no cache] 500 found

338) Cytochrome P450 enzymes are responsible for the metabolism of >75% of marketed drugs, making it essential to identify the contributions of individual cytochromes P450 to the total clearance of a new candidate drug.

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PMID:34183376 DOI:10.1124/dmd.120.000320

2021 Drug metabolism and disposition: the biological fate of chemicals

* Development of Robust Quantitative Structure-Activity Relationship Models for CYP2C9, CYP2D6, and CYP3A4 Catalysis and Inhibition.

- Cytochrome P450 enzymes are responsible for the metabolism of Cytochrome P450 enzymes are responsible for the metabolism of >75% of marketed drugs, making it essential to identify the contributions of individual cytochromes P450 to the total clearance of a new candidate drug.gt;75% of marketed drugs, making it essential to identify the contributions of individual cytochromes P450 to the total clearance of a new candidate drug. Overreliance on one cytochrome P450 for clearance levies a high risk of drug-drug interactions; and considering that several human cytochrome P450 enzymes are polymorphic, it can also lead to highly variable pharmacokinetics in the clinic. Thus, it would be advantageous to understand the likelihood of new chemical entities to interact with the major cytochrome P450 enzymes at an early stage in the drug discovery process. Typical screening assays using human liver microsomes do not provide sufficient information to distinguish the specific cytochromes P450 responsible for clearance. In this regard, we experimentally assessed the metabolic stability of ∼5000 compounds for the three most prominent xenobiotic metabolizing human cytochromes P450, i.e., CYP2C9, CYP2D6, and CYP3A4, and used the data sets to develop quantitative structure-activity relationship models for the prediction of high-clearance substrates for these enzymes. Screening library included the NCATS Pharmaceutical Collection, comprising clinically approved low-molecular-weight compounds, and an annotated library consisting of drug-like compounds. To identify inhibitors, the library was screened against a luminescence-based cytochrome P450 inhibition assay; and through crossreferencing hits from the two assays, we were able to distinguish substrates and inhibitors of these enzymes. The best substrate and inhibitor models (balanced accuracies ∼0.7), as well as the data used to develop these models, have been made publicly available (https://opendata.ncats.nih.gov/adme) to advance drug discovery across all research groups. SIGNIFICANCE STATEMENT: In drug discovery and development, drug candidates with indiscriminate cytochrome P450 metabolic profiles are considered advantageous, since they provide less risk of potential issues with cytochrome P450 polymorphisms and drug-drug interactions. This study developed robust substrate and inhibitor quantitative structure-activity relationship models for the three major xenobiotic metabolizing cytochromes P450, i.e., CYP2C9, CYP2D6, and CYP3A4. The use of these models early in drug discovery will enable project teams to strategize or pivot when necessary, thereby accelerating drug discovery research.

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(1)271 of	(8)4 volume	(15)2 WMS	(22)2 drug-related
(2)9 number	(9)3 costs	(16)2 active	(23)2 hemoglobin
(3)8 OH	(10)3 knee	(17)2 amount	(24)2 intracranial
(4)6 energy	(11)3 mean	(18)2 cholesterol	(25)2 plasma
(5)4 body	(12)3 radioactivity	(19)2 cholesterol,	(26)2 variation
(6)4 protein	(13)2 null	(20)2 clearance
(7)4 the	(14)2 72	(21)2 data

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--- WordNet output for total --- =>1.(車が)全壊する, 全損する, 2.全体の, 全ての, 総計の, 総体の, 全くの, 完全な, 総力の, 3.総額, 総計, 全体の, (車が)全壊する, 合計(する), なる Overview of noun total The noun total has 2 senses (first 2 from tagged texts) 1. (13) sum, total, totality, aggregate -- (the whole amount) 2. (6) sum, amount, total -- (a quantity obtained by the addition of a group of numbers) Overview of verb total The verb total has 3 senses (first 2 from tagged texts) 1. (16) total, number, add up, come, amount -- (add up in number or quantity; "The bills amounted to $2,000"; "The bill came to $2,000") 2. (2) total, tot, tot up, sum, sum up, summate, tote up, add, add together, tally, add up -- (determine the sum of; "Add all the people in this town to those of the neighboring town") 3. total -- (damage beyond the point of repair; "My son totaled our new car"; "the rock star totals his guitar at every concert") Overview of adj total The adj total has 2 senses (first 2 from tagged texts) 1. (31) entire, full, total -- (constituting the full quantity or extent; complete; "an entire town devastated by an earthquake"; "gave full attention"; "a total failure") 2. (2) full, total -- (complete in extent or degree and in every particular; "a full game"; "a total eclipse"; "a total disaster") --- WordNet end ---