Carvedilol serves as a novel CYP1B1 inhibitor, a systematic drug repurposing approach through structure-based virtual screening and experimental verification

Ying Wang; Xiaomei He; Chunshi Li; Yan Ma; Wenchi Xue; Baichun Hu; Jian Wang; Tingting Zhang; Fengjiao Zhang

doi:10.1016/j.ejmech.2020.112235

Carvedilol serves as a novel CYP1B1 inhibitor, a systematic drug repurposing approach through structure-based virtual screening and experimental verification

Eur J Med Chem. 2020 May 1:193:112235. doi: 10.1016/j.ejmech.2020.112235. Epub 2020 Mar 16.

Authors

Ying Wang¹, Xiaomei He¹, Chunshi Li², Yan Ma¹, Wenchi Xue¹, Baichun Hu², Jian Wang², Tingting Zhang¹, Fengjiao Zhang³

Affiliations

¹ Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China.
² Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China.
³ Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China. Electronic address: zhangfengjiao@syphu.edu.cn.

PMID: 32203789
DOI: 10.1016/j.ejmech.2020.112235

Abstract

Cytochrome P450 1B1 (CYP1B1) is a promising target for prevention and therapy of cancer, particularly those with drug resistance, stimulating cancer cell survival, and promoting cancer resistance. In view of the extreme complexity and high risk in drug discovery and development, a drug repurposing strategy was applied in the present study to find potential CYP1B1 inhibitors through structure-based virtual screening in the FDA database. Intriguingly, after a thorough assessment of docking scores, binding affinities, as well as binding modes, six compounds were highlighted for further verification. In fact, both carvedilol and indacaterol showed inhibitory activity towards human CYP1B1 with the IC₅₀ of 1.11 μM and 59.52 μM, respectively, according to EROD assay; however, neither docking score nor the detailed binding mode of carvedilol in the hit pose dictated to be a superior CYP1B1 inhibitor to indacaterol, which called for the necessity to re-access the binding mode of carvedilol. Thus, the top two representative docking poses of carvedilol were re-assessed. Indeed, compared to the one hit in the virtual screening (due to a false positive Glide gscore), the other docking pose exhibited ideal performance in both molecular dynamics (MD) simulation, binding free energy, and density functional theory (DFT) calculation evaluations. This identification of the exact binding pose of carvedilol is not only essential for a better understanding of the mechanism underlying its activity, but also contributes to uncovering the structure-activity relationship of CYP1B1 inhibitors. Of note, carvedilol exhibited direct cytotoxicity against both human lung adenocarcinoma epithelial cell line A459 and its Taxol-resistant subline (A549/Taxol). In particular, it showed superior toxicity towards A549/Taxol cells that overexpressed CYP1B1, which further supported its potential to be an effective CYP1B1 inhibitor.

Keywords: CYP1B1; Carvedilol; DFT; Drug repurposing; Molecular dynamics simulation; Virtual screening.

MeSH terms

A549 Cells
Carvedilol / chemistry
Carvedilol / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Cytochrome P-450 CYP1B1 / antagonists & inhibitors*
Cytochrome P-450 CYP1B1 / chemistry
Cytochrome P-450 CYP1B1 / metabolism
Density Functional Theory
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Drug Repositioning
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Enzyme Inhibitors
Carvedilol
CYP1B1 protein, human
Cytochrome P-450 CYP1B1