In silico profiling of histone deacetylase inhibitory activity of compounds isolated from Cajanus cajan

Kayode Adewole,Ige Olaoye,Adebayo Ishola

doi:10.1186/s43088-021-00191-y

Abstract

BackgroundCancer is responsible for high morbidity and mortality globally. Because the overexpression of histone deacetylases (HDACs) is one of the molecular mechanisms associated with the development and progression of some diseases such as cancer, studies are now considering inhibition of HDAC as a strategy for the treatment of cancer. In this study, a receptor-based in silico screening was exploited to identify potential HDAC inhibitors among the compounds isolated from Cajanus cajan, since reports have earlier confirmed the antiproliferative properties of compounds isolated from this plant.ResultsCajanus cajan-derived phytochemicals were docked with selected HDACs, with givinostat as the reference HDAC inhibitor, using AutodockVina and Discovery Studio Visualizer, BIOVIA, 2020. Furthermore, absorption, distribution, metabolism and excretion (ADME) drug-likeness analysis was done using the Swiss online ADME web tool. From the results obtained, 4 compounds; betulinic acid, genistin, orientin and vitexin, were identified as potential inhibitors of the selected HDACs, while only 3 compounds (betulinic acid, genistin and vitexin) passed the filter of drug-likeness. The molecular dynamic result revealed the best level of flexibility on HDAC1 and HDAC3 compared to the wild-type HDACs and moderate flexibility of HDAC7 and HDAC8.ConclusionsThe results of molecular docking, pharmacokinetics and molecular dynamics revealed that betulinic acid might be a suitable HDAC inhibitor worthy of further investigation in order to be used for regulating conditions associated with overexpression of HDACs. This knowledge can be used to guide experimental investigation on Cajanus cajan-derived compounds as potential HDAC inhibitors.

Highlights

Cancer is responsible for high morbidity and mortality globally
The results of molecular docking, pharmacokinetics and molecular dynamics revealed that betulinic acid might be a suitable Histone deacetylase (HDAC) inhibitor worthy of further investigation in order to be used for regulating conditions associated with overexpression of HDACs
3 Results The binding affinities obtained from the molecular docking of the 13 C. cajan derived-compounds revealed that four compounds have higher binding affinities for HDAC1 and HDAC 3 relative to the standard inhibitor, givinostat, with the values indicated in bold values (Table 1)

Summary

Introduction

Cancer is responsible for high morbidity and mortality globally. Because the overexpression of histone deacetylases (HDACs) is one of the molecular mechanisms associated with the development and progression of some diseases such as cancer, studies are considering inhibition of HDAC as a strategy for the treatment of cancer. Among plant foods that have attracted interest as a functional food is Cajanus cajan (pigeon pea) because of Adewole et al Beni-Suef Univ J Basic Appl Sci (2022) 11:9 have reported that extracts and compounds isolated from C. cajan possess antiinflammatory, antioxidative, antibacterial, hypoglycemic, hypocholesterolemic and antiproliferative effects [3, 7, 8] Such studies have reported the antiproliferative effects of C. cajan extracts and its bioactive compounds on different cancer cell lines, including human breast adenocarcinoma (MCF-7), human cervical adenocarcinoma (HeLa), human colorectal adenocarcinoma (Caco-2), human lung cancer (A549), and human hepatoma (HepG2) cells [3, 8,9,10, 12]. Specific examples are seen in the regulation of cell cycle by HDACs 1, and 3, over expression of HDAC1 in gastric, breast, prostate and colon cancers [20, 21], over expression of HDAC2 in gastric, cervical and colorectal cancers [22, 23], overexpression of HDAC3 in colon cancer [21], over activities of HDAC2 and HDAC3 in breast tumors [24], over expression of HDAC8 in childhood neuroblastoma [25] as well as the involvement of HDAC1 and HDAC8 in breast cancer metastasis [17]

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Conclusion