Dembitsky VM (2021), In Silico Prediction of Steroids and Triterpeno...

ECB-ART-50668

Mar Drugs 2021 Nov 22;1911:. doi: 10.3390/md19110650.

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In Silico Prediction of Steroids and Triterpenoids as Potential Regulators of Lipid Metabolism.

Dembitsky VM .

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This review focuses on a rare group of steroids and triterpenoids that share common properties as regulators of lipid metabolism. This group of compounds is divided by the type of chemical structure, and they represent: aromatic steroids, steroid phosphate esters, highly oxygenated steroids such as steroid endoperoxides and hydroperoxides, α,β-epoxy steroids, and secosteroids. In addition, subgroups of carbon-bridged steroids, neo steroids, miscellaneous steroids, as well as synthetic steroids containing heteroatoms S (epithio steroids), Se (selena steroids), Te (tellura steroids), and At (astatosteroids) were presented. Natural steroids and triterpenoids have been found and identified from various sources such as marine sponges, soft corals, starfish, and other marine invertebrates. In addition, this group of rare lipids is found in fungi, fungal endophytes, and plants. The pharmacological profile of the presented steroids and triterpenoids was determined using the well-known computer program PASS, which is currently available online for all interested scientists and pharmacologists and is currently used by research teams from more than 130 countries of the world. Our attention has been focused on the biological activities of steroids and triterpenoids associated with the regulation of cholesterol metabolism and related processes such as anti-hyperlipoproteinemic activity, as well as the treatment of atherosclerosis, lipoprotein disorders, or inhibitors of cholesterol synthesis. In addition, individual steroids and triterpenoids were identified that demonstrated rare or unique biological activities such as treating neurodegenerative diseases, Alzheimer's, and Parkinson's diseases with a high degree of certainty over 95 percent. For individual steroids or triterpenoids or a group of compounds, 3D drawings of their predicted biological activities are presented.

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References [+] :

Abdel Bar, Antiproliferative triterpenes from Melaleuca ericifolia. 2008, Pubmed

	Figure 1. Bioactive aromatic steroids demonstrating with dominance of antihypercholesterolemia and antiovulation activity.
	Figure 2. The 3D graph (X (a) and Y (b) views) shows the predicted and calculated antiovulation activity of aromatic steroids (compound numbers: 7, 9, 1, 8, and 10) showing the highest degree of confidence, more than 92.5%. These steroids are derived from animals, including humans, as well as the extract of bark from the main wooden rod of ketapang Terminalia catappa, and can be used in clinical medicine as potential agents with strong ovulation inhibitors. The units of measurement of the x–y digits (Cos–Sin or Sin–Sin) are the relative dimensions that the Origin Pro 2021 graphics program chooses independently, depending on the data obtained by the PASS program. On the 3D graphs, the Origin Pro software in red indicates the maximum biological activity of an individual steroid, and blue indicates the minimum activity.
	Figure 3. The 3D graph shows the predicted pharmacological activities of 2-hydroxyestrone (7). 2-Hydroxyestrone (2-OHE1) or 2.3-estracatechol, also known as estra-1,3,5(10)-trien-2,3-diol-17-one, is an endogenous, naturally occurring catechol estrogen that was first isolated from human urine more than 60 years ago [106], apparently as a product of estrone and estradiol metabolism. According to the PASS data, 2-hydroxyestrone is the strongest ovulation inhibitor among aromatic steroids. In addition, it is a cardiovascular analeptic and can be used as a drug for the treatment and prevention of male reproductive dysfunction, menopausal disorders in women, as well as treatment of muscular dystrophy.
	Figure 4. The 3D graph showing the predicted and calculated antihypercholesterolemic activity of aromatic steroids (compound numbers: 6, 13, 11, 14, 15, and 19) with the highest degree of confidence, more than 94.6%. These steroids have been obtained from a variety of natural sources, including plant, fungal, and marine invertebrate extracts, and appear to be useful in clinical medicine as potential agents with potent antihypercholesterolemic activity.
	Figure 5. The 3D graph shows the predicted pharmacological activities of estriol 3-glucuronide (6). The water-soluble conjugate of estriol, also known as estriol 3-β-D-glucosiduronic acid, is a naturally occurring steroidal estrogen containing β-D-glucopyranuronic acid that was first discovered and isolated from the urine of women in the late 1930s [107,108,109]. According to the PASS data, estrone glucuronide, in addition to the main antihypercholesterolemic activity (97.3%), is also a potent regulator of lipid metabolism with a reliability of 90.7% and can be used to treat acute neurological disorders (92.2%).
	Figure 6. Bioactive natural, semi-synthetic, and synthetic steroid phosphate esters.
	Figure 7. The 3D graph showing the predicted pharmacological activities of tremasterol A (21). Data from the PASS program show that phosphated steroid glycoside named tremasterol A exhibits 20 different biological activities, with dominant properties as a wound healing agent. Interestingly, tremasterol A is isolated from the starfish Trenzaster novaecaledoniae. This is a rare occasion when glycosides from starfish demonstrate such beneficial biological activities.
	Figure 8. The 3D graph showing the predicted pharmacological activities of the sitostanol derivative (30). This drug has antihypercholesterolemic and antihyperlipoproteinemic properties that help lower cholesterol levels in the human body and reduce the risk of strokes and heart attacks. In addition, the drug is a strong cholesterol absorption inhibitor with a confidence level of 95.7% and a regulator of lipid metabolism with a confidence level of 95.4% and can be used to treat acute neurological disorders.
	Figure 9. Secosteroids showing activity as lipid metabolism regulators.
	Figure 10. The 3D graph shows the predicted pharmacological activities of compound (40). This secosteroid is characterized by antihypercholesterolemic properties. In addition, it exhibits hepatoprotective properties, and it is an inhibitor of cell proliferation, which de facto can prevent several pathological diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, and liver cirrhosis.
	Figure 11. The 3D graph showing the predicted pharmacological activities of ergocalciferol (39). A secosterol hormone called ergocalciferol was first isolated as a radiation product of 7-dehydrocholesterol and described in 1936 by Windaus and co-workers [149]. Ergocalciferol is an important drug and is recommended by the World Health Organization. In addition, it has anticancer, anti-inflammatory, and antieczema properties, and can also be recommended as an antihypercholesterolemic agent and an agent against Parkinson’s disease. Certain foods, such as breakfast cereals and margarine, contain ergocalciferol in some countries, and it is found in the lichen Cladina arbuscula and alfalfa (Medicago sativa) [150,151,152,153,154].
	Figure 12. Bioactive α,β-epoxy steroids derived from marine sources.
	Figure 13. The 3D graph shows the predicted and calculated biological activity of α,β-epoxy steroids (compound numbers: 42, 44, and 48) showing the highest degree of confidence, more than 92.4%.
	Figure 14. Bioactive steroid endoperoxides derived from marine sources and fungi.
	Figure 15. Bioactive steroid hydroperoxides derived from plants.
	Figure 16. The 3D graph shows the predicted and calculated biological activity of steroid hydroperoxides (compound numbers: 59, 63, and 66) showing the highest degree of confidence, more than 93%.
	Figure 17. Bioactive CBS derived from fungi and marine sources.
	Figure 18. The 3D graph shows the predicted and calculated biological activity of carbon-bridged steroids (compound numbers: 70, 74, and 78) showing the highest degree of confidence, more than 95%.
	Figure 19. Bioactive neo steroids derived from plants and marine sources.
	Figure 20. The 3D graph shows the predicted and calculated biological activity of neo steroids (compound numbers: 81, 86, 89, and 93) showing the highest degree of confidence, more than 96.9%.
	Figure 21. Bioactive steroids derived from soft corals.
	Figure 22. The 3D graph shows the predicted and calculated biological activity of soft coral steroids (compound numbers: 99, 101 and 104) showing the highest degree of confidence, more than 96.2%.
	Figure 23. Bioactive epithio steroids and triterpenoid containing the thiirane group in a variety of steroid backbones.
	Figure 24. The 3D graph shows the predicted and calculated biological activity of triterpenod (116), which was synthesized from a natural sample of 18β-glycyrrhetinic acid, showing the highest degree of confidence as lipid metabolism regulator properties, more than 95.4%. 18β-Glycyrrhetinic acid is a β-amyrin-type pentacyclic triterpenoid derived from the herb licorice (Glycyrrhiza glabra). It is known and used as a flavoring agent and masks the bitter taste of drugs such as aloe and quinine; it is also effective in the treatment of peptic ulcer disease and has some additional pharmacological properties with possible antiviral, antifungal, antiprotozoal, and antibacterial effects.
	Figure 25. Bioactive synthetic selena steroids.
	Figure 26. The 3D graph shows the predicted and calculated biological activity of the selena steroids (compound numbers: 120, 121 and 122) showing the highest degree of confidence, more than 99.5%.
	Figure 27. Bioactive synthetic tellura steroids.
	Figure 28. The 3D graph shows the predicted and calculated biological activity of the tellura steroid (129) showing the highest degree of confidence, more than 99.5%. This tellura steroid is interesting, in that it is a rare case when any chemical compound shows simultaneously such activities as prevention and treatment of neurodegenerative diseases Alzheimer’s and Parkinson’s with strong confidence, over 94 percent. In addition, this steroid demonstrated antioxidant and antihypercholesterolemic activities, and can also be used as a potential drug for the treatment of atherosclerosis. The maximum values of various biological activities are shown in red.
	Figure 29. Biological active synthetic astatosteroids.
	Figure 30. The 3D graph shows the predicted and calculated biological activity of the astatosteroid (133) showing the highest degree of confidence, more than 97.6%. Moreover, it can also be used as a potential drug for the treatment of bone diseases.