Article
Pharmacology & Pharmacy
Hong-can Ren, Yang Sai, Tao Chen, Chun Zhang, Lily Tang, Cheng-guang Yang
Summary: The study developed a PBPK-DDI model to predict drug-drug interactions co-administrated with ketoconazole in humans. Through verification with actual data, the model showed good predictive performance with predicted results within the observed range, and significantly better accuracy compared to traditional mechanistic models.
Article
Biochemistry & Molecular Biology
Petar M. Mitrasinovic
Summary: The study revealed that chrysin has the largest inhibitory effect on CYP3A4, while quercetin and flavopiridol serve as representative examples of structurally different flavonoids. The inhibition parameters for these compounds were evaluated using the calibrated QM/MM strategy, aiding in quantitatively understanding the functional behavior of the whole flavonoid family. Additionally, a kinetic threshold for further assessment of the time-dependent inhibition of CYP3A4 by flavonoids was explored.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Chemistry, Analytical
Michael Riffle, Michael R. Hoopmann, Daniel Jaschob, Guo Zhong, Robert L. Moritz, Michael J. MacCoss, Trisha N. Davis, Nina Isoherranen, Alex Zelter
Summary: The study introduces Magnum and Limelight, an algorithm and software package for the identification and visualization of xenobiotic-protein adducts. Through validation and application, the methods and software enable accurate identification of xenobiotic-protein adducts and fill the gap in comprehensive data visualization tools in the field of open-mass searching.
ANALYTICAL CHEMISTRY
(2022)
Article
Plant Sciences
Saneesh Kumar, Patrick J. Bouic, Bernd Rosenkranz
Summary: The study evaluated the effects of Withania somnifera root extracts on cytochromes P450, finding that they may cause clinically significant herb-drug interactions by affecting the metabolism pathway of drugs such as rifampicin.
JOURNAL OF ETHNOPHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Laura Maria Fuhr, Fatima Zahra Marok, Uwe Fuhr, Dominik Selzer, Thorsten Lehr
Summary: Grapefruit is a potent inhibitor of CYP3A4, which can affect the metabolism of CYP3A4 victim drugs for up to 24 hours after consumption. This study developed a physiologically-based pharmacokinetic model to simulate and predict the effect of grapefruit juice on the plasma concentration-time profiles of various CYP3A4 victim drugs.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2023)
Review
Pharmacology & Pharmacy
Fengling Wang, Xue Zhang, Yanyan Wang, Yunna Chen, Huiyu Lu, Xiangyun Meng, Xi Ye, Weidong Chen
Summary: Cytochrome P450 3A4 (CYP3A4) plays a crucial role in the metabolism of many drugs, especially anticancer drugs. The activity and expression of CYP3A4 greatly affect the pharmacological activities and clinical outcomes of these drugs. However, there is still limited understanding of the factors influencing CYP3A4-mediated drug metabolism, leading to interindividual variability and potential adverse events. This review focuses on elucidating the underlying determinants of CYP3A4 activity and discusses the challenges and opportunities for optimizing dosing regimens in personalized cancer therapy.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Chemistry, Physical
Nico D. Fessner, Christopher Grimm, Matic Srdic, Hansjoerg Weber, Wolfgang Kroutil, Ulrich Schwaneberg, Anton Glieder
Summary: This study explores the synthetic potential of human P450 3A4 in diversifying natural product classes, resulting in the identification of 31 authentic human metabolites. With efficient expression levels in P. pastoris, this biocatalyst shows promising results for modifying natural products in a one-step fashion.
Article
Biochemistry & Molecular Biology
Ilia G. Denisov, Yelena V. Grinkova, Mark A. McLean, Tyler Camp, Stephen G. Sligar
Summary: Human cytochrome P450 CYP3A4 plays a significant role in the metabolism of more than 35% of pharmaceuticals, leading to drug-drug interactions. This study evaluated the use of midazolam as a probe substrate to detect and predict the involvement of new drug candidates in CYP3A4-mediated drug-drug interactions. The results suggest that the changes in the shape and volume of the substrate-binding pocket explain the occurrence of drug interactions.
Article
Biophysics
Kevin F. dos Santos, Elsa M. Materon, Osvaldo N. Oliveira Jr
Summary: This study investigated the influence of cytochrome P450 3A4 (CYP3A4) on the interaction between the drug doxorubicin (DOX) and cell membranes. The results showed that the lipid composition plays a crucial role in this interaction, and that the presence of CYP3A4 significantly reduces the effect of DOX on the cell membranes. These findings support the idea that CYP3A4 is involved in drug resistance and suggest potential strategies to enhance the efficacy of chemotherapy.
COLLOIDS AND SURFACES B-BIOINTERFACES
(2022)
Article
Pharmacology & Pharmacy
Bettina Gerner, Fatemeh Aghai-Trommeschlaeger, Sabrina Kraus, Goetz Ulrich Grigoleit, Sebastian Zimmermann, Max Kurlbaum, Hartwig Klinker, Nora Isberner, Oliver Scherf-Clavel
Summary: This study developed a PBPK model to investigate the drug-drug interaction between POS and RUX. The research found that when used in combination with POS, RUX exposure increased, suggesting the need for further dose adjustments.
Article
Pharmacology & Pharmacy
Vladimir Mishin, Diane E. Heck, Yi-Hua Jan, Jason R. Richardson, Jeffrey D. Laskin
Summary: A characteristic of cytochrome P450 (CYP) enzymes is their ability to produce H2O2, which can lead to cellular oxidative stress and tissue damage. This study aimed to determine if specific form inhibitors could differentiate between the monooxygenase and NADPH oxidase activities of CYP enzymes. The findings suggest that form-specific inhibitors can effectively distinguish these two activities.
TOXICOLOGY AND APPLIED PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Yanjun Feng, Changda Gong, Jieyu Zhu, Guixia Liu, Yun Tang, Weihua Li
Summary: CYP3A4 is a major drug-metabolizing enzyme in the human body, responsible for metabolizing approximately 50% of clinically used drugs. This study used docking-based approaches with geometric features to predict the sites of metabolism for CYP3A4 substrates. Analysis of a large dataset of 474 substrates revealed a widely observed geometric pattern called the close proximity of sites of metabolism. Several structure-based models were constructed based on this pattern, demonstrating better performance than models based on Fe-SOM distance. To further improve prediction performance, the structure-based models were combined with the ligand-based model SMARTCyp, resulting in one combined model that showed good performance on an external substrate set.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Shiwei Lu, Feng Zhang, Jiahao Gong, Jian Huang, Guanghao Zhu, Yitian Zhao, Qi Jia, Yiming Li, Bo Li, Kaixian Chen, Weiliang Zhu, Guangbo Ge
Summary: This study discovered potent and orally active hCYP3A4 inhibitors from chalcone derivatives and tested their effects on hCYP3A4 in vitro and in vivo. The isoquinoline chalcones were found to have excellent anti-hCYP3A4 effects after screening and optimization. SAR studies revealed the structural requirements for enhancing the anti-CYP3A4 effect. A lead compound, C6, was identified as the most potent hCYP3A4 inhibitor and showed good metabolic stability and safety profiles. In vivo tests demonstrated the efficacy of C6 in increasing drug exposure and prolonging drug half-life. Overall, this study offers valuable insights into developing novel CYP3A4 inhibitors.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Review
Biochemistry & Molecular Biology
Kenza Mansoor, Razan Bardees, Bayan Alkhawaja, Eyad Mallah, Luay AbuQatouseh, Mathias Schmidt, Khalid Matalka
Summary: Pomegranate juice contains a variety of polyphenols that have numerous health benefits. However, it can interact with certain drugs, affecting their metabolism and efficacy. Current research focuses on the impact of pomegranate juice on CYP3A4 and CYP2C9 metabolized drugs.
Article
Biochemistry & Molecular Biology
F. Peter Guengerich, Kevin D. McCarty, Jesse G. Chapman
Summary: Cytochrome P450 (P450) 3A4 is a crucial enzyme in drug metabolism, with certain inhibitors showing distinct kinetic characteristics in inhibiting its activity. The exact mechanisms of P450 3A4 inhibition by various drugs are still unclear in many cases.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
John J. Morrison, David A. Crosby, Denis J. Crankshaw
EUROPEAN JOURNAL OF PHARMACOLOGY
(2016)
Article
Obstetrics & Gynecology
D. J. Crankshaw, Y. M. O'Brien, D. A. Crosby, J. J. Morrison
JOURNAL OF PERINATOLOGY
(2017)
Article
Obstetrics & Gynecology
Denis J. Crankshaw, David A. Crosby, John J. Morrison
REPRODUCTIVE SCIENCES
(2017)
Article
Obstetrics & Gynecology
Eva M. Sweeney, Denis J. Crankshaw, Yvonne O'Brien, Peter Dockery, John J. Morrison
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
(2013)
Article
Chemistry, Medicinal
James McNulty, Jerald J. Nair, Nesrin Vurgun, Benjamin R. DiFrancesco, Carla E. Brown, Bernice Tsoi, Denis J. Crankshaw, Alison C. Holloway
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2012)
Article
Chemistry, Medicinal
James McNulty, Alexander J. Nielsen, Carla E. Brown, Benjamin R. DiFrancesco, Nesrin Vurgun, Jerald J. Nair, Denis J. Crankshaw, Alison C. Holloway
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2013)
Article
Chemistry, Medicinal
James McNulty, Kunal Keskar, Denis J. Crankshaw, Alison C. Holloway
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2014)
Article
Pharmacology & Pharmacy
Denis J. Crankshaw, Eva M. Sweeney, Yvonne M. O'Brien, Jennifer M. Walsh, Peter Dockery, John J. Morrison
EUROPEAN JOURNAL OF PHARMACOLOGY
(2014)
Article
Anatomy & Morphology
Eva M. Sweeney, Peter Dockery, Denis J. Crankshaw, Yvonne M. O'Brien, Jennifer M. Walsh, John J. Morrison
JOURNAL OF ANATOMY
(2014)
Article
Medicine, Research & Experimental
Denis J. Crankshaw, Jennifer M. Walsh, John J. Morrison
Article
Obstetrics & Gynecology
Denis J. Crankshaw, Marc J. Pistilli, Yvonne M. O'Brien, Eva M. Sweeney, Peter Dockery, Alison C. Holloway, John J. Morrison
REPRODUCTIVE SCIENCES
(2013)
Article
Obstetrics & Gynecology
Gillian A. Ryan, Sarah M. Nicholson, Denis J. Crankshaw, John J. Morrison
JOURNAL OF PERINATOLOGY
(2019)
Article
Chemistry, Medicinal
Alexander J. Nielsen, Sergio Raez-Villanueva, Denis J. Crankshaw, Alison C. Holloway, James McNulty
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2019)
Article
Obstetrics & Gynecology
Gillian A. Ryan, Sarah M. Nicholson, Denis J. Crankshaw, John J. Morrison
Summary: Women with a history of vaginal delivery show significantly greater contractile parameters of human myometrium compared to those without, including maximum amplitude, force, and rate of rise and relaxation of contractions. These differences may partially explain clinical variances observed during labor.
AMERICAN JOURNAL OF PERINATOLOGY
(2021)
Article
Obstetrics & Gynecology
Gillian A. Ryan, Denis J. Crankshaw, John J. Morrison
EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY
(2019)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
