Molecular insight on the formation structure and dynamics of melatonin in an aqueous solution and at the Water-Air interface: A molecular dynamics study

Published on Wednesday, 09 February 2022

Abstract

Melatonin is a natural hormone that has been shown highly antioxidant effects. Consequently, it has been extensively studied for its therapeutic potential in several diseases such as insomnia, cardiovascular, Alzheimer, and certain types of cancers. Recently, it has been used to adjuvant treatment for COVID-19 patients.

It is well-known that melatonin is highly hydrophobic, resulting in lower solubility.

However, the molecular structure and dynamic behavior of the formation of melatonin in an aqueous solution and at the water-air interface have not yet been clearly explained. This information is necessary for the melatonin formulation in drug delivery systems. The present work focuses on the molecular structure and dynamics of melatonin molecules in the aqueous solution and at the water-air interface based on using a molecular dynamics simulation study.

The results showed that most melatonin molecules were aggregated in an aqueous solution while they were formed a self-assembled monolayer with the ordered structure at the water-air interface. The strong interaction of melatonin depends on their functional group which showed a similar trend for both systems and was sequenced as follows: carbonyl O > indole NH > amide NH > methoxy OA, respectively. However, the carbonyl O and the indole NH groups exhibit strong interactions with water molecules at the interface. Consequently, the two preferred orientations of the melatonin head group can be observed at the water-air interface (i.e., one is to turn the head group to the water surface with the tilted angle of ~40°-60° and the second one is to turn the head group away from the water surface with the tilted angle of ~130°).

The longer lifetime of hydrogen bonds formed between melatonin themselves in the bulk water reveals that the stability of melatonin aggregation in an aqueous solution is more stable. Therefore, melatonin has less soluble in an aqueous solution.

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- The Di Bella Method (A Fixed Part - Melatonin tablets. From 30-40mg/day up to 200mg/day orally in patients with advanced stage of cancer disease and/or patients without respond to traditional treatments);

- Melatonin use in cancer patients have started in 1974, when melatonin prepared according to Prof. Di Bella’s formulation [...]. For 11 days was administered to the patient, admitted to the general medical ward at the Maggiore-Pizzardi Hospital in Bologna, very slowly (over approx. 8 hours) and intravenously administered 1000 mg of melatonin for 11 days. During the course of each day, the patient was intravenously administered 4 saline drips of 500 ml, each containing ten 25 mg bottles of freeze-dried melatonin, lasting 2 hours, totaling 1000 mg per day. No other drug of any kind was administered in order to ascertain the effect of the MLT without interference [...]. From Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;

- About Melatonin - In vitro, review and in vivo publications;

- Publication: Melatonin anticancer effects: Review (from Di Bella's Foundation);

- Publication: Key aspects of melatonin physiology: 30 years of research (from Di Bella's Foundation);

- The Synergism of Somatostatin, Melatonin, Vitamins Prolactin and Estrogen Inhibitors Increased Survival, Objective Response and Performance Status In 297 Cases of Breast Cancer;

- Complete objective response, stable for 5 years, with the Di Bella Method, of multiple-metastatic carcinoma of the breast;

- Evaluation of the safety and efficacy of the first-line treatment with somatostatin combined with melatonin, retinoids, vitamin D3, and low doses of cyclophosphamide in 20 cases of breast cancer: a preliminary report;

- The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 122 cases of breast cancer;

- Complete objective response to biological therapy of plurifocal breast carcinoma;

- Recurrent Glioblastoma Multiforme (grade IV – WHO 2007): a case of complete objective response achieved by means of the concomitant administration of Somatostatin and Octreotide – Retinoids – Vitamin E – Vitamin D3 – Vitamin C – Melatonin – D2 R agonists (Di Bella Method – DBM) associated with Temozolomide;

- The Di Bella Method DBM improved survival objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck;

- Chronic Lymphocytic Leukemia: Long-Lasting Remission with Combination of Cyclophosphamide, Somatostatin, Bromocriptine, Retinoids, Melatonin, and ACTH;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced non-small-cell lung cancer patients with low performance status;