In Silico Study of the 5-Hydroxytryptamine-2C Receptor Antagonist Activity of Anthocyanins as Antidepressant Therapy

Nia Kurnianingsih, Novita Titis Harbiyanti, Ardani Galih Prakosa, Retty Ratnawati
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Abstract

This study aimed to evaluate the drug-likeness, pharmacokinetic and safety prediction of six types of anthocyanins (ANC) as well as virtual molecular interaction between ANC and 5-hydroxytryptamine-2C (5HT-2C) receptor for antagonist target of antidepressant drug development. The Lipinski rule of five was used to predict the oral drug-likeness of ANC. The pharmacokinetic and safety prediction was analyzed with a free accessible web server. The ligands of ANC were retrieved from PubChem National Centre for Biotechnology Information (NCBI) database. The protein of the 5HT-2C receptor was obtained from Protein Data Bank. Molecular docking was performed by PyRx software and visualized using Discovery Studio Software. The results showed ANC is proposed as an oral drug candidate. The pharmacokinetic prediction of ANC was demonstrated to have high absorption in the intestinal route, solubility in the aqueous phase, capability to evade hepatic first-pass metabolism and high total clearance from the kidney. Virtual toxicity prediction showed a higher threshold of chronic lethal dose than control with no toxicity on the salmonella typhimurium reverses mutation assay (AMES) test, liver, and skin. Molecular prediction found ANC type of delphinidin has the most similar interaction site with the control antagonist ligand on the 5HT-2C receptor which is facilitated with hydrogen bonds and hydrophobic bonds at amino residues of Trp324, Phe328, Ala222 and Val135. We concluded ANC particularly delphinidin is proposed as an oral drug candidate potentially used as a 5HT-2C receptor antagonist and thus, further in vitro and in vivo studies are necessary to confirm the effect on antidepressant activity.
花青素抗抑郁治疗5-羟色胺- 2c受体拮抗剂活性的硅片研究
本研究旨在评价6种花青素(ANC)的药物相似性、药代动力学和安全性预测,以及ANC与5-羟色胺- 2c (5HT-2C)受体作为抗抑郁药物拮抗靶点的虚拟分子相互作用。采用利平斯基五法则预测ANC的口服药物相似性。通过免费访问的web服务器分析药代动力学和安全性预测。ANC的配体检索自PubChem国家生物技术信息中心(NCBI)数据库。5HT-2C受体蛋白来源于protein Data Bank。通过PyRx软件进行分子对接,并使用Discovery Studio软件进行可视化。结果表明,ANC可作为一种口服候选药物。ANC的药代动力学预测被证明具有肠路吸收高、水相溶解度高、能够逃避肝脏第一次代谢和肾脏总清除率高的特点。虚拟毒性预测显示鼠伤寒沙门菌反向突变试验(AMES)、肝脏和皮肤的慢性致死剂量阈值高于无毒性的对照组。分子预测发现ANC型飞鸽素与5HT-2C受体上对照拮抗剂配体的相互作用位点最为相似,在Trp324、Phe328、Ala222和Val135的氨基残基上存在氢键和疏水键促进作用。我们的结论是,ANC特别是飞燕草苷被建议作为一种口服候选药物,可能用作5HT-2C受体拮抗剂,因此,需要进一步的体外和体内研究来证实其抗抑郁活性的作用。
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