Cardioprotective Melatonin: Translating from Proof-of-Concept Studies to Therapeutic Use

Abstract

In this review we summarized the actual clinical data for a cardioprotective therapeutic role of melatonin, listed melatonin and its agonists in different stages of development, and evaluated the melatonin cardiovascular target tractability and prediction using machine learning on ChEMBL. To date, most clinical trials investigating a cardioprotective therapeutic role of melatonin are in phase 2a. Selective melatonin receptor agonists Tasimelteon, Ramelteon, and combined melatonergic-serotonin Agomelatine, and other agonists with registered structures in CHEMBL were not yet investigated as cardioprotective or cardiovascular drugs. As drug-able for these therapeutic targets, melatonin receptor agonists have the benefit over melatonin of well-characterized pharmacologic profiles and extensive safety data. Recent reports of the X-ray crystal structures of MT1 and MT2 receptors shall lead to the development of highly selective melatonin receptor agonists. Predictive models using machine learning could help to identify cardiovascular targets for melatonin. Selecting ChEMBL scores > 4.5 in cardiovascular assays, and melatonin scores > 4, we obtained 284 records from 162 cardiovascular assays carried out with 80 molecules with predicted or measured melatonin activity. Melatonin activities (agonistic or antagonistic) found in these experimental cardiovascular assays and models include arrhythmias, coronary and large vessel contractility, and hypertension. Preclinical proof-of-concept and early clinical studies (phase 2a) suggest a cardioprotective benefit from melatonin in various heart diseases. However, larger phase 3 randomized interventional studies are necessary to establish melatonin and its agonists' actions as cardioprotective therapeutic agents.

Keywords: cardioprotection; cardiovascular system; drugs; in silico; machine learning; melatonin.

Figure 1

Melatonin mechanisms of action.

Figure 2

Comparison of the melatonin potency score for MTR1B vs. MTR1A, and MTR1 vs. MTR1A.

Figure 3

Machine learning schema for melatonin activity.

Figure 4

Correlation for regression between the actual and predicted melatonin activity scores (right) and the count ratio. Color is by actual classification label (red = active, yellow = inactive). CountRatio bar chart inset is the same chart zooming in the active zone.

Figure 5

Activity distribution histogram for the 1.5 M compounds.

Figure 6

Diagram of the interaction of predicted melatonin active molecules on different models of cardiovascular assays. In red: CV assay model, blue: molecule. When the molecule has a drug name, this name is displayed. When the molecule has a simple registry number it is hidden to allow better visualization.