scholarly journals In Vitro approach for identification of a leading cytochrome P450 isoenzyme responsible for biotransformation of novel arylpiperazine drug candidates and their inhibition potency towards CYP3A4.

2020 ◽  
Vol 77 (1) ◽  
pp. 69-76
Author(s):  
Szymon Ulenberg ◽  
Mariusz Belka ◽  
Paweł Georgiev ◽  
Marek Król ◽  
Franciszek Herold ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Candidates ◽  
Cytochrome P450 Isoenzyme ◽  
Inhibition Potency

scholarly journals In Vitro Interactions between New Antitubercular Drug Candidates SQ109 and TMC207

2010 ◽  
Vol 54 (7) ◽  
pp. 2840-2846 ◽  
Author(s):  
Venkata M. Reddy ◽  
Leo Einck ◽  
K. Andries ◽  
Carol A. Nacy
Keyword(s):  
Cytochrome P450 ◽  
Area Under The Curve ◽  
Antitubercular Drug ◽  
Postantibiotic Effect ◽  
Antitubercular Drugs ◽  
Drug Candidates ◽  
Single Drug ◽  
Cytochrome P450 Genes ◽  
In Vitro Interactions

ABSTRACT The in vitro interactions of two new antitubercular drugs, SQ109 and TMC207, with each other and with rifampin (RIF) were evaluated. The combination of SQ109 with TMC207 (i) improved an already excellent TMC207 MIC for M. tuberculosis H37Rv by 4- to 8-fold, (ii) improved the rate of killing of bacteria over the rate of killing by each single drug, and (iii) enhanced the drug postantibiotic effect by 4 h. In no instance did we observe antagonistic activities with the combination of SQ109 and TMC207. Rifampin activates cytochrome P450 genes to reduce the area under the curve (AUC) for TMC207 in humans. The presence of RIF in three-drug combinations did not affect the synergistic activities of SQ109 and TMC207, and SQ109 also dramatically decreased the MIC of RIF. SQ109 was active by itself, and both its activity was improved by and it improved the in vitro activities of both RIF and TMC207.

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.

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

2019 ◽  
Vol 26 (25) ◽  
pp. 4799-4831 ◽  
Author(s):  
Jiahua Cui ◽  
Xiaoyang Liu ◽  
Larry M.C. Chow
Keyword(s):  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Drug Candidates ◽  
Chemical Structures ◽  
Transporter Family ◽  
Promising Area ◽  
New Generation ◽  
Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Drug Candidates ◽  
Lead Compounds ◽  
New Drug ◽  
Compound Libraries ◽  
Screening Assays ◽  
Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

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.

scholarly journals Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody–drug conjugates as lead drug candidates for clinical trials

2020 ◽  
Vol 12 ◽  
pp. 175883592092006
Author(s):  
Hang-Ping Yao ◽  
Sreedhar Reddy Suthe ◽  
Xiang-Min Tong ◽  
Ming-Hai Wang
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Targeted Therapeutics ◽  
Antibody Drug Conjugates ◽  
Drug Candidates ◽  
Drug Conjugates ◽  
Ron Receptor ◽  
Antibody Drug

The recepteur d’origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.

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