Cytochrome P450-Mediated Epoxidation of 2-Aminothiazole-Based AKT Inhibitors: Identification of Novel GSH Adducts and Reduction of Metabolic Activation through Structural Changes Guided by in Silico and in Vitro Screening

Cytochrome P450 monooxygenase CYP51 (sterol 14α-demethylase) is a well-known target of the azole drug fluconazole for treating cryptococcosis, a life-threatening fungal infection in immune-compromised patients in poor countries. Studies indicate that mutations in CYP51 confer fluconazole resistance on cryptococcal species. Despite the importance of CYP51 in these species, few studies on the structural analysis of CYP51 and its interactions with different azole drugs have been reported. We therefore performed in silico structural analysis of 11 CYP51s from cryptococcal species and other Tremellomycetes. Interactions of 11 CYP51s with nine ligands (three substrates and six azoles) performed by Rosetta docking using 10,000 combinations for each of the CYP51-ligand complex (11 CYP51s × 9 ligands = 99 complexes) and hierarchical agglomerative clustering were used for selecting the complexes. A web application for visualization of CYP51s’ interactions with ligands was developed (http://bioshell.pl/azoledocking/). The study results indicated that Tremellomycetes CYP51s have a high preference for itraconazole, corroborating the in vitro effectiveness of itraconazole compared to fluconazole. Amino acids interacting with different ligands were found to be conserved across CYP51s, indicating that the procedure employed in this study is accurate and can be automated for studying P450-ligand interactions to cater for the growing number of P450s.

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Integrated in silico–in vitro screening of ovarian cancer peroxisome proliferator-activated receptor-γ agonists against a biogenic compound library

Medicinal Chemistry Research ◽

10.1007/s00044-017-2060-1 ◽

2017 ◽

Vol 27 (1) ◽

pp. 341-349 ◽

Cited By ~ 2

Author(s):

Gui-Lian Zhang ◽

Feng-Ying Liu ◽

Jing Zhang ◽

Li-Ping Wang ◽

Er-Xia Jia ◽

...

Keyword(s):

Ovarian Cancer ◽

In Silico ◽

Peroxisome Proliferator ◽

In Vitro Screening ◽

Compound Library ◽

Peroxisome Proliferator Activated Receptor ◽

Biogenic Compound

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New acetylphenol-based acyl thioureas broaden the scope of drug candidates for urease inhibition: synthesis, in vitro screening and in silico analysis

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2021.12.064 ◽

2021 ◽

Author(s):

Urage Zahra ◽

Sumera Zaib ◽

Aamer Saeed ◽

Mujeeb ur Rehman ◽

Ghulam Shabir ◽

...

Keyword(s):

In Silico ◽

In Silico Analysis ◽

In Vitro Screening ◽

Urease Inhibition ◽

Drug Candidates ◽

Silico Analysis

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Which cytochrome P450 metabolizes phenazepam? Step by step in silico, in vitro, and in vivo studies

Drug Metabolism and Personalized Therapy ◽

10.1515/dmpt-2017-0036 ◽

2018 ◽

Vol 33 (2) ◽

pp. 65-73 ◽

Cited By ~ 6

Author(s):

Dmitriy V. Ivashchenko ◽

Anastasia V. Rudik ◽

Andrey A. Poloznikov ◽

Sergey V. Nikulin ◽

Valeriy V. Smirnov ◽

...

Keyword(s):

Cell Culture ◽

Cytochrome P450 ◽

In Silico ◽

In Vivo Studies ◽

Cyp3a Activity ◽

Cell Culture Study ◽

Study Results ◽

Three Stages

Abstract Background: Phenazepam (bromdihydrochlorphenylbenzodiazepine) is the original Russian benzodiazepine tranquilizer belonging to 1,4-benzodiazepines. There is still limited knowledge about phenazepam’s metabolic liver pathways and other pharmacokinetic features. Methods: To determine phenazepam’s metabolic pathways, the study was divided into three stages: in silico modeling, in vitro experiment (cell culture study), and in vivo confirmation. In silico modeling was performed on the specialized software PASS and GUSAR to evaluate phenazepam molecule affinity to different cytochromes. The in vitro study was performed using a hepatocytes’ cell culture, cultivated in a microbioreactor to produce cytochrome P450 isoenzymes. The culture medium contained specific cytochrome P450 isoforms inhibitors and substrates (for CYP2C9, CYP3A4, CYP2C19, and CYP2B6) to determine the cytochrome that was responsible for phenazepam’s metabolism. We also measured CYP3A activity using the 6-betahydroxycortisol/cortisol ratio in patients. Results: According to in silico and in vitro analysis results, the most probable metabolizer of phenazepam is CYP3A4. By the in vivo study results, CYP3A activity decreased sufficiently (from 3.8 [95% CI: 2.94–4.65] to 2.79 [95% CI: 2.02–3.55], p=0.017) between the start and finish of treatment in patients who were prescribed just phenazepam. Conclusions: Experimental in silico and in vivo studies confirmed that the original Russian benzodiazepine phenazepam was the substrate of CYP3A4 isoenzyme.

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Practical and computational studies on novel Schiff base complexes derived from green synthesis approach: Conductometry as well as in-vitro screening supported by in-silico study

Journal of Molecular Liquids ◽

10.1016/j.molliq.2020.114116 ◽

2020 ◽

Vol 319 ◽

pp. 114116 ◽

Cited By ~ 2

Author(s):

Reem Shah ◽

Hanadi Katouah ◽

Anas A. Sedayo ◽

Matokah Abualnaja ◽

Meshari M. Aljohani ◽

...

Keyword(s):

Schiff Base ◽

Green Synthesis ◽

In Silico ◽

Schiff Base Complexes ◽

Computational Studies ◽

In Vitro Screening ◽

In Silico Study ◽

Synthesis Approach

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Screening of cytochrome P450 3A4 inhibitors via in silico and in vitro approaches

RSC Advances ◽

10.1039/c8ra06311g ◽

2018 ◽

Vol 8 (61) ◽

pp. 34783-34792 ◽

Cited By ~ 3

Author(s):

Xiaocong Pang ◽

Baoyue Zhang ◽

Guangyan Mu ◽

Jie Xia ◽

Qian Xiang ◽

...

Keyword(s):

Cytochrome P450 ◽

Virtual Screening ◽

In Silico ◽

Cytochrome P450 3A4 ◽

Important Member ◽

Cyp3a4 Inhibitors

Cytochrome P450 3A4 (CYP3A4) is an important member of the CYP family and responsible for metabolizing a broad range of drugs. It is necessary to establish virtual screening models for predicting CYP3A4 inhibitors.

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