Assessing the therapeutic potential of agomelatine, ramelteon, and melatonin against SARS-CoV-2

Pradeep Kumar Yadalam; Thodur Madapusi Balaji; Saranya Varadarajan; Khalid J Alzahrani; Mohammad S Al-Ghamdi; Hosam Ali Baeshen; Mohammed Farhan A Alfarhan; Zohaib Khurshid; Shilpa Bhandi; Raghunathan Jagannathan; Vikrant R Patil; A Thirumal Raj; Jithendra Ratnayake; Shankargouda Patil

doi:10.1016/j.sjbs.2022.01.049

Assessing the therapeutic potential of agomelatine, ramelteon, and melatonin against SARS-CoV-2

Saudi J Biol Sci. 2022 May;29(5):3140-3150. doi: 10.1016/j.sjbs.2022.01.049. Epub 2022 Jan 25.

Authors

Affiliations

¹ Department of Periodontics, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
² Department of Periodontology, Tagore Dental College and Hospital, Chennai, India.
³ Department of Oral Pathology and Microbiology, Sri Venkateswara Dental College and Hospital, Chennai, India.
⁴ Department of Clinical Laboratories Sciences,College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia.
⁵ Department of Orthodontics, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia.
⁶ Department of Surgery, College of Medicine, King Faisal University, Al-Ahsa, Saudi Arabia.
⁷ Department of Prosthodontics and Dental Implantology, College of Dentistry, King Faisal University, Al-Ahsa, Saudi Arabia.
⁸ Department of Restorative Dental Science, College of Dentistry, Jazan, University, Saudi Arabia.
⁹ Department of Periodontology, Tagore Dental College and Hospital, Chennai 600127, India.
¹⁰ Biogenre Private Limited, Pune, India.
¹¹ Department of Oral Science, Faculty of Dentistry, University of Otago, 310 Great King Street, Dunedin 9016, New Zealand.
¹² Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan, Saudi Arabia.

Abstract

Background: The SARS-Cov-2(severe acute respiratory syndrome coronavirus 2) infection affecting human populations worldwide is now a very concerning issue considering the morbidity and mortality rates. Despite several measures followed by the medical fraternity and general public, there is no resolution. Therapeutic measures to tackle the infection have been based on researching new designer drug molecules that could prevent viral entry into the human host. Melatonin has been tried as an adjuvant in the management of COVID 19(coronavirus disease) illness but its specific antiviral role has not been investigated. Objectives: The objectives of the present study were to conduct an in-silico analysis to investigate if melatonin and related drugs namely ramelteon and agomelatine could be used as antiviral agents in SARS-CoV-2 infection based on their binding to the SARS-CoV-2 receptor binding site (RBD) and Angiotensin-converting enzyme 2 (ACE 2).

Methods: For docking studies (Pdb Id 1M0J), the SARS-CoV-2 spike protein receptor-binding domain (RBD) crystal structure which was ACE2 cell receptor bounded was employed. From the PubChem database, the three-dimensional configuration of the ligands melatonin, ramelteon, and agomelatine was retrieved, and conceptual density functional theory (CDFT) was performed to determine molecular descriptors. Charges were added and optimized with the universal force field to prepare the ligands for the process of docking. For facilitation of readability by the AutoDock software conversion to PDBQT(Protein Data Bank, Partial Charge (Q), & Atom Type (T)) format was performed. AutoDock version 4.2.6 docking program and AutoDock Tools (ADT) version 1.5.6 were used for molecular docking. Desmond, a Package of Schrödinger LLC was used to simulate molecular dynamics for hundred nanoseconds using.

Results: Data from the present study reveal that melatonin, ramelteon, and agomelatine demonstrate significant binding with SARS-CoV-2 RBD and ACE 2 demonstrating the fact that they can strongly prevent viral entry into the host cells through dual binding effects. However, Ramelteon was found to be the most superior amongst the 3 drugs analyzed in its antiviral properties against SARS-CoV-2.

Conclusion: Results advocate further research in exploring the potential therapeutic applications of melatonin, ramelteon, and agomelatine for the management of SARS-CoV-2 infection.

Keywords: ACE 2; In silico; Melatonin; SARS-CoV-2; Spike protein.