In silico drug discovery of melatonin receptor ligands with therapeutic potential

ABSTRACT

Introduction

The neurohormone melatonin (N-acetyl-5-methoxytryptamine) regulates circadian rhythms exerting a variety of effects in the central nervous system and in periphery. These activities are mainly mediated by activation of MT₁ and MT₂ GPCRs. MT₁/MT₂ agonist compounds are used clinically for insomnia, depression, and circadian rhythm disturbances.

Area covered

The following review describes the design strategies that have led to the identification of melatonin receptor ligands, guided by in silico approaches and molecular modeling. Initial ligand-based design, mainly relying on pharmacophore modeling and 3D-QSAR, has been flanked by structure-based virtual screening, given the recent availability of MT₁ and MT₂ crystal structures. Receptor ligands with different activity profiles, agonist/antagonist and subtype-selective compounds, are available.

Expert opinion

An insight on the pharmacological characterization and therapeutic perspectives for relevant ligands is provided. In silico drug discovery has been instrumental in the design of novel ligands targeting melatonin receptors. Ligand-based approaches has led to the construction of a solid framework defining structure-activity relationships to obtain compounds with a tailored pharmacological profile. Structure-based techniques could integrate previous knowledge and provide compounds with novel chemotypes and pharmacological activity as drug candidates for disease conditions in which melatonin receptor ligands are currently being investigated, including cancer and pain.

KEYWORDS:

• Circadian rhythm
• docking
• 3D-QSAR
• drug design
• pharmacophore
• melatonin
• melatonin receptors
• sleep disorders
• virtual screening

Article Highlights

• Melatonin is a neurohormone mainly produced by the pineal gland at night that entrains circadian rhythms to environmental time cues.

• Melatonin exerts most of its physiological and neuroendocrine activities through activation of the high affinity G-protein-coupled receptors MT₁ and MT₂.

• Melatonin receptor agonists are used for the treatment of insomnia, circadian rhythms, and mood disorders.

• MT₁ and MT₂ receptor ligands are currently being investigated in several disease conditions, such as cancer, pain, diabetes, and obesity.

• Several agonist, antagonist, inverse agonist, and subtype-selective receptor ligands have been obtained through ligand-based drug design. Some have progressed to preclinical studies and few agonists to clinical evaluation.

• Docking into the MT₁ and MT₂ crystal structures allowed the virtual screen of large libraries of compounds and the identification of ligands with novel chemotypes and activities that might be further developed into drug candidates.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Italian Ministry for University and Research (MIUR, PRIN 2017, project 20175SA5JJ).