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

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.


Introduction
Lipids are a complex name for many metabolites of natural origin, and they are combined into various groups according to a common physical property, hydrophobicity, that is, insolubility in water [1][2][3][4]. However, this definition is currently not entirely correct, since some groups, phospholipids or sphingolipids and some others, manifest themselves as amphiphilic compounds; that is, they can dissolve both in polar substances and in non-polar solvents [5][6][7][8].
Lipids play an important role in the body in storing energy and are components of biological membranes, steroid hormones, bile acids, and vitamins. They come from food or de novo synthesis in the liver. Fatty acids, stored primarily as triglycerides, are the main source of energy for the muscles and heart. However, the overproduction and accumulation of triglycerides in adipose tissue and other tissues are closely associated with metabolic disorders in humans. Disorders of lipid metabolism lead to the development of many diseases, including atherosclerosis, which occurs because of a violation of cholesterol homeostasis and is closely associated with atherosclerosis [9,10]. In addition, estrogen and estrogen receptors are well-known regulators of several aspects of metabolism, including glucose and lipid metabolism, and impairment of estrogen signaling is associated with the development of metabolic diseases [11].
The regulation of lipid metabolism is of interest primarily in the context of the regulation of energy flow and the way of its integration with other energy sources in tissues. A special role in the regulation of lipid metabolism is played by hormones such as adrenaline and norepinephrine, glucagon, glucocorticoids, hormones of the anterior pituitary gland, as well as thyroxine and sex hormones [12][13][14][15][16][17][18][19][20].
This review is devoted to natural, semi-synthetic and synthetic steroids, and triterpenoids isolated from plants, fungi, marine invertebrates, and synthesized in various laboratories around the world. The presented class of molecules differs from many other steroids or triterpenoids that exhibit a wide range of biological activities aimed at lowering cholesterol by inhibiting cholesterol synthesis or other activities associated with these processes.

Aromatic Steroids Derived from Natural Sources
The most famous natural monoaromatic steroids that are of some practical interest in terms of regulators of lipid metabolism are estrone (1), estradiol (2), estriol (3), and equilin (4). The chemical structures of these aromatic steroids are shown in Figure 1. It is known that estrone is a minor female sex hormone, which was discovered in the 1920s from the urine of pregnant women independently by two groups of scientists from Germany and the United States, biochemist Adolph Butenandt and American scientists Edward Doisy and Edgar Allen, respectively [21][22][23][24][25][26][27][28]. Later, Adolf Frederik Johann Butenandt from the Institute of Chemistry in Götting (Germany) received the Nobel Prize in Chemistry in 1939 for the discovery of this hormone.
From the 1930s to the present, more than 15,000 articles have been devoted to various issues of estrone and its derivatives, and more than 200 reviews summarize the data on the activity of this hormone. Estrone (1) and estradiol (2) and their derivatives (3)(4)(5)(6)(7)(8)(9)(10) are the main natural estrogens found in humans and are involved in estrogen metabolism [35][36][37][38]. Endogenous estrogens in humans demonstrate a wide range of biological activities and are involved in the regulation of lipid metabolism, which has been the subject of tens of thousands of articles, reviews, and books. Additionally, in this short paragraph, we will not list and discuss this topic, but in Table 1, we give a short list of the main biological activities that aromatic steroids show. Aromatic steroids found in animals and humans are also produced by some marine invertebrates and are found in the extracts of certain plants and fungi, as well as in marine sediments. Thus, the extract of bark from the main wooden rod of ketapang Terminalia catappa (family Combretaceae) contained estrone (1), estriol (3), equilin (4), equilin sulfate (5), and (11) [39]. The ethanol extract of leaves of T. catappa shows antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans, as well as antifungal activity against Epidermophyton floccosum and C. albicans [40][41][42]. In addition, extracts of leaves and roots and other parts have been studied for many medicinal properties and have shown antidiabetic, wound healing, anti-inflammatory, anticancer, antimicrobial, hepatoprotective, and antioxidant activities [43]. Unusual withanolide (20S,22R)-1,6β,17α,27-tetrahydroxy19norwitha-1,3,5(10),24-tetraenolide, named jaborosalactone 7- (12), was isolated from the leaf extracts of Juborosa leucotricha [44].
Monoaromatic B ring steroids are rare natural lipids found predominantly in the mushroom kingdom and are also present in marine sediments or oils. Thus, phycomysterol A (17) and C (18), which possess a unusual natural 19-norergostane skeleton with an aromatic B ring, are synthesized by a filamentous fungus Phycomyces blakesleeanus (order Mucorales, the phylum Zygomycota) [50]. In addition, phycomysterol A showed antiviral inhibition at a concentration of 0.64 µg per well (200 µL) and showed (IC 50 = 5.0 µg/mL) against both mouse lymphomas (IC 50 = 10 µg/mL) and against the three human cell lines, A549 (lung carcinoma), HT29 (colon carcinoma), and MEL28 (melanoma) human cell lines.
Pathogenic fungus Gibberella zeae (syn. Fusarium roseum) is a worldwide parasite that can produce a wide variety of steroids and synthesized unusual (22E,24R)-1(10→6)abeoergosta-5,7,9,22-tetraen-3α-ol (19), which was isolated from the cultures of Gibberella zeae, an endophytic fungus isolated from the marine green alga Codium fragile [51]. This compound showed significant cytotoxicity toward murine colorectal CT26 and human leukemia K562 cancer cell lines. An aromatic B ring called topsentisterol E1 (20) was isolated from bioactive fractions of a marine sponge Topsentia sp. [52]. The presence of this unusual steroid may indicate that it is synthesized by the endophytic fungus, which is a symbiont in this sponge species.

Comparison of Biological Activities of Natural Aromatic Steroids
It is known that the chemical structure of both natural and synthetic molecules predetermines biological activity, which makes it possible to analyze the structure-activity relationships (SAR). This idea was first proposed by Brown and Fraser more than 150 years ago, in 1868 [53], although, according to other sources, SAR originates from the field of toxicology, according to which Cros in 1863 determined the relationship between the toxicity of primary aliphatic alcohols and their solubility in water [54]. More than 30 years later, Richet in 1893 [55], Meyer in 1899 [56], and Overton in 1901 [57] separately found a linear correlation between lipophilicity and biological effects. By 1935, Hammett [58,59] presented a method of accounting for the effect of substituents on reaction mechanisms using an equation that considered two parameters, namely the substituent constant and the reaction constant. Complementing Hammett's model, Taft proposed in 1956 an approach for separating the polar, steric, and resonance effects of substituents in aliphatic compounds [60]. Combining all previous developments, Hansch and Fujita laid out the mechanistic basis for the development of the QSAR method [61], and the linear Hansch equation and Hammett's electronic constants are detailed in the book by Hansch and Leo published in 1995 [62].
Some well-known computer programs can, with some degree of reliability, estimate the pharmacological activity of organic molecules isolated from natural sources or synthesized compounds [63][64][65]. It is known that classical SAR methods are based on the analysis of (quantitative) structure-activity relationships for one or more biological activities using organic compounds belonging to the same chemical series as the training set [66].
The computer program PASS, which has been continuously updating and improving for the past thirty years [67], is based on the analysis of a heterogeneous training set included information about more than 1.3 million known biologically active compounds with data on ca. 10,000 biological activities [68,69]. Chemical descriptors implemented in PASS, which reflect the peculiarities of ligand-target interactions and original realization of the Bayesian approach for 18 elucidations of structure-activity relationships, provide the average accuracy and predictivity for several thousand biological activities equal to about 96% [70]. In several comparative studies, it was shown that PASS outperforms in predictivity some other recently developed methods for estimation of biological activity profiles [71,72]. Freely available via the Internet, the PASS Online web service [73] is used by more than thirty thousand researchers from almost a hundred countries to determine the most promising biological activities for both natural and synthetic compounds [74][75][76]. To reveal the hidden pharmacological potential of the natural substances, we have successfully been using PASS for the past fifteen years [77][78][79][80].  [103][104][105] Pa values, which correspond to the probability of belonging to a class of "actives" for each predicted biological activity. The higher the Pa value is, the higher the confidence that the experiment will confirm the predicted biological activity [78,80]. The study of the biological activity of aromatic steroids using the PASS program showed that all steroids presented in Table 1 can be divided into two groups. The first group includes steroids that show antiovulation activity with a high degree of reliability, and the second group includes steroids for which antihypercholesterolemic activity is dominant. The first group includes aromatic steroids numbered 7, 9, 1, 8, and 10 with over 92.5 percent confidence, although the second group includes steroids 6, 11, 13, 14, 15, and 19 with over 94.6 percent confidence, according to PASS.
A 3D graph of the predicted and calculated activities of aromatic steroids belonging to the first group is shown in Figure 2. From the first group of steroids that are inhibitors of ovulation, 2-hydroxyestrone (7) can be distinguished, which has a confidence level of more than 95%, and its predicted activities are presented in Figure 3. Additionally, 3D graphs that demonstrate the predicted pharmacological activity were obtained using the Origin Pro 2021 graphical program. The program analyzes the data obtained by the PASS program and builds graphs that are given in this publication.  . 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.
Among the second group of aromatic steroids that demonstrate strong antihypercholesterolemic activity, and a 3D graph of predicted and calculated antihypercholesterolemic activity is shown in Figure 4; the strongest steroid is estrone glucuronide (6), and a 3D graph of its predicted pharmacological activities is shown in Figure 5. 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. 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%).

Natural, Semi-, and Synthetic Steroid Phosphate Esters
Steroid phosphate esters are rare lipid molecules that can form the building blocks of biological membranes and have been found more recently in starfish extracts. So, for the first time, steroid phosphates were discovered more than a quarter of a century ago by Italian scientists from the University of Frederico II, in the city of Napoli. Unique steroids were isolated from the extract of the polar lipids of the starfish Tremaster novaecaledoniae, which was collected at a depth of 530 m of New Caledonia [110]. The isolated phosphated steroid glycosides were called tremasterols A and C, and their structures were identified as 3β-O-sulphated, 6α-O-phosphated, and 16β-O-acetylated groupings on a steroidal skeleton (21,22, and 23).
Synthetic steroids, such as testosterone 17β-phosphate (24), cortisol 21-phosphate (25), and cholesterol 3β-phosphate (26), were chosen by us for comparison of biological activity with the activity of steroids isolated from marine invertebrates [111]. Testosterone 17β-phosphate (24) is an androgen and belongs to the class of anabolic steroids and is used for intramuscular injection, and it is a substrate for phosphatases in the phosphatase pool of the prostate [112]. Cortisol 21-phosphate (25) refers to the glucocorticoid class of hormones, and it functions to increase blood sugar levels through gluconeogenesis and to promote the metabolism of fats, proteins, and carbohydrates, and it is a substrate for alkaline phosphatase and is used for an enzyme immunoassay for human chorionic gonadotropin, human growth hormone, and α-fetoprotein and estradiol [113]. Cholesterol 3β-phosphate (26) promotes normalization of blood pressure and plays an important role in atherogenesis [114,115].
Two novel cholesterol-lowering agents called sodium ascorbic campestanol phosphate (27) and sodium ascorbic sitostanol phosphate (28) were synthesized, and their properties were studied [116]. Using Western blot analysis of P-GP expression, it was shown that changes in mdr-1 gene expression lead to correlating changes in P-GP protein expression. More recently, two steroid phosphate esters (29 and 30, structures see on Figure 6 and activities on Table 2) have been synthesized, acting as inhibitors of cholesterol biosynthesis. Methods of treating or preventing various diseases, conditions, and disorders by administering these steroids or compositions are also provided [117]. Estradiol phosphate (31) is ester of estrogen with phosphoric acid and acts as a prodrug of estradiol in the human body. In medical practice, both drugs can be used to treat prostate cancer [118].  Remedy for the treatment of prostate cancer [118] * Only activities with Pa > 0.5 are shown.

Comparison of Biological Activities of Steroid Phosphate Esters
According to PASS, antihypercholesterolemic activity is characteristic of all steroid phosphate esters presented in Table 2 with varying degrees of confidence. In addition, all steroids are inhibitors of cholesterol synthesis, except for steroid 31. However, some lipid steroidal molecules such as 21-23 can be agents for wound healing and hepato-protectors with a high degree of certainty, and steroids 23-28 and 31 also demonstrate the properties of a neuroprotective agent with a high degree of certainty from 90 to 98%.
Steroid phosphate esters are of great practical interest in medicine, as they are wound healing agents. The confidence level of steroid 21 is 97.5%. Figure 7 shows the 3D graph of biological activities with a dominant property as a wound healing agent.  (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.
The sitostanol derivative (30) was synthesized by scientists from British Columbia (Canada) as a strong inhibitor of cholesterol synthesis, and as shown by the PASS data, this lipid molecule is in fact an excellent drug for the treatment of atherosclerosis. The wide range of biological activities of the sitostanol derivative (30) is shown in Figure 8.  (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.

Highly Oxygenated Natural Steroids and Triterpenoids
Highly oxygenated steroids are a large group of steroids and triterpenoids found in plant, fungal, and invertebrate extracts, and many of them exhibit a wide range of biological activities. This group of lipids includes secosteroids, epoxy steroids and peroxy steroids, and triterpenoids, which demonstrate a high degree of activity as potential regulators of lipid metabolism [119][120][121][122][123].

Secosteroids Derived from Marine and Terrestrial Sources
Secosteroids are a large group of natural steroidal hormones with a so-called 'broken' ring by oxidation of rings A, B, C, or D. Typical representatives of secosteroids are fatsoluble vitamins of group D [124][125][126][127]. Secosteroids are found in plant and animal extracts, produced by fungi, and found in marine invertebrates and algae [121,[128][129][130].

Comparison of Biological Activities of Secosteroids
Among the secosteroids shown in Figure 9, which show activity as regulators of lipid metabolism, the most interesting is lipid molecule number 40, which has aAntihypercholesterolemic activity with a confidence level of 97.7 percent. Figure 10 shows the 3D graph of the predicted pharmacological activities of this steroid. Ergocalciferol (39) or vitamin D2 is also of great interest, as PASS showed strong antiparkinson activity with a confidence level of 96.0%. The full spectrum of the predicted pharmacological activities of ergocalciferol is shown in the 3D graph in Figure 11.  (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].

Comparison of Biological Activities of α,β-Epoxy Steroids Derived from Marine Sources
Comparing the data from the PASS obtained for the α, β-epoxy steroids presented in Table 4, it can be concluded that there are no outstanding steroids with lipid metabolism regulator properties; then, we present in Figure 13 a comparative 3D graph for this subgroup of steroids.

Peroxy-Type Steroids Derived from Natural Sources
Natural and/or synthetic compounds containing a peroxy group (R-O-O-R) are called peroxides [166][167][168][169][170][171][172]. Natural peroxides represent a rather large group of compounds that many microorganisms produce, and they have also been found in plants, mushrooms, animals, and marine invertebrates [166][167][168]. Peroxy steroids are a small group of natural lipids, mainly found in leaves, roots, and bark of plants, and are produced by fungal endophytes and are found in mushrooms [166,167,173].

Steroid Endoperoxides
Astropecten polyacanthus starfish extract has significant cytotoxic effects and contains an unusual peroxy steroid called astropectenol B (49) was isolated from a methanol extract of this starfish [174].
Fuscoporianol D (53) was found in field-grown mycelia of fungus Inonotus obliquus (family Hymenochaetaceae) [179]. Ergosterol peroxide 3-O-β-D-glucopyranoside (54) produced by fungus Tremella fuciformis [180] and same compound was detected in the fruiting bodies of the Chinese toxic woodland mushroom Naematoloma fasciculare [181]. Endoperoxy steroid 55 was found in popular mushroom in Japan, Buna shimeji and in oyster fungus Pleurotus ostreatus [182]. Two endoperoxy glycosides (55 and 56) were found in ethanol extracts of the fungus Lactarius volemus, which demonstrated anticancer activity [183,184]. The chemical structures of steroids are shown in Figure 14, and the biological activity is shown in Table 5.

Steroid and Triterpenoid Hydroperoxides
A flowering herbaceous perennial plant from the family Araceae, Arum italicum, also known as Italian arum and Italian lords-and-ladies, contains a suite of hydroperoxysterols, including two (57 and 58) that are interesting for lipid metabolism [185]. Two steroids (59 and 60), which showed a cytotoxic effect against several human cancer cell lines, have been isolated from the bark of the chinaberry tree, Melia azedarach [186]. The chemical structures of steroids are shown in Figure 15, and the biological activity is shown in Table 6. Ponce and co-workers obtained ergosterol 7-hydroperoxide (61) by the photo-oxidation of ergosterol with singlet oxygen in vivo and in vitro [187]. In addition, the yeast Saccharomyces cerevisiae with the singlet oxygen leads to rapid oxidation of ergosterol to ergosterol 7-hydroperoxide (61) [188].
Analysis of PASS data on peroxy steroids and triterpenoids such as endoperoxides and hydroperoxides showed that most of these lipids have a high confidence level of more than 90 percent, but nevertheless, only three of all peroxy steroids deserve attention; these are steroids numbered 59, 63, and 66, which have a confidence level of over 93 percent. Figure 16 presents the 3D graph showing the predicted and calculated biological activity of steroid hydroperoxides.

Carbon-Bridged Steroids (CBS) and Triterpenoids
In both natural and synthetic steroids, when an additional ring is formed within the steroid skeleton, through a direct bond between any two carbon atoms (or more) of the steroid ring system or an attached side chain, such steroids (or triterpenoids) are called carbon-bridged steroids [13,[200][201][202].
Of the more than 500 carbon-bridged steroids and triterpenoids studied, we found only twelve lipids that have a confidence level of more than 90 percent as potential lipid regulators. We give their description and their sources in nature below [13,203].

Comparison of Biological Activities of CBS Steroids and Triterpenoids
Carbon-bridged steroids (CBS) and triterpenoids belong to a rare group of natural hormones found in various natural sources such as green, yellow-green, and red algae, sea sponges, soft corals, ascidians, starfish, and other marine invertebrates. In addition, this group of rare lipids is found in amoebas, fungi, fungal endophytes, and plants [13,203].
We have isolated carbon-bridged steroids presented in Figure 18, which, according to the PASS data, have a confidence level of more than 90 percent. Among this group of lipids, we identified three, numbered 70, 74, and 78, the activity of which most clearly reflects their regulatory functions of lipid metabolism, with antihypercholesterolemic properties dominating. In addition, these steroids can be used as inhibitors of cholesterol synthesis and as drugs for the treatment of atherosclerosis. The 3D graph demonstrating the predicted and calculated biological activity of carbon-bridged steroids is shown in Figure 18.  : 70, 74, and 78) showing the highest degree of confidence, more than 95%.
Neo steroids are a small group of lipids that are synthesized by yeast and fungi and are found in various parts of plants. In recent years, with the improvement of steroid anal-ysis methods, they have been found in seaweeds, marine sponges (class Demospongiae), anemones (class Anthozoa), and cucumbers (class Holothuroidea) [12,219].
Two neo steroids (79 and 85) were present in leaves and stems and the pericarp of the fruit and roots of a plant from the family Cucurbitaceae [222], and another sterol, 24-methylene-25-methyl-lathosterol (80), was isolated from aerial parts of the herbaceous plant, Sicyos angulatus [223]. The chemical structures of steroids and triterpenoids are shown in Figure 19, and the biological activity is shown in Table 8. Aerial parts of the strongly aromatic herb Ocimum basilicum from the Labiatae family, such as seeds, flowers, and roots, are widely used as medicines [224][225][226]. The leaves and flowers of this plant are used in folk medicine as a tonic and anthelmintic [227]. Leaf tea is used to treat flatulence and dysentery, while the plant's oil may be useful for relieving mental fatigue, colds, cramps, rhinitis, and as a first aid for treating wasp stings and snake bites [227,228]. A species of this plant from Pakistan contains (22E)-24ξ-ethyl-25methylcholesta-5,22-diene-3β-ol-3-O-D-gluco-pyranoside (81) [229].

Comparison of Biological Activities of Neo Steroids
Neo steroids are a rare group of naturally occurring lipid molecules that exhibit high levels and a wide range of activities. The chemical structures shown in Figure 19 have been found in plant and marine invertebrate extracts. According to PASS data, neo steroids show a high confidence level of up to 98.9 percent, with antihypercholesterolemic activity being dominant. In addition, virtually all neo steroids are cholesterol synthesis inhibitors and can be used to treat atherosclerosis and related diseases.
Of the seventeen neo steroids, we have selected four that show a high confidence level of 96.9 to 98.9 percent. Figure 20 demonstrates the 3D graph and 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%.  : 81, 86, 89, and 93) showing the highest degree of confidence, more than 96.9%.

Miscellaneous Steroids and Triterpenoids Derived from Marine Sources
In this section, we have collected steroids that do not belong to the first six groups of triterpenoids but show high antihypercholesterolemic activity. Mostly, the steroids shown in Figure 20 are found in soft corals collected in various regions of the world's oceans.
An interesting question is why from coral? The fact is that, by studying the activities of various marine organisms, we concluded that corals or their fungal endophytes synthesize many biologically active metabolites. It is well known that corals are associated with many microscopic fungi, so a reasonable question arises: what synthesizes bioactive molecules in corals? Whether they do so themselves or their fungal endophytes or bacteria is a question that remains open [240][241][242].

Comparison of Biological Activities of Soft Coral Steroids
The chemical and structural diversity of soft corals sterols and triterpenoids is well known and has been documented in several review articles in the literature [128,130,[257][258][259][260][261]. PASS analysis shows that the steroids in Figure 21 synthesized by soft corals are indeed of interest due to their high anticholesterol activity. Both the biological activities found using PASS and those obtained experimentally coincide. In addition, we have identified three steroids, numbered 99, 101, and 104, which demonstrate antihypercholesterolemic activity with a high degree of certainty. Figure 22 shows a 3D graph of predicted and calculated biological activity of these steroids.

Synthetic and Semi-Synthetic Steroids and Triterpenoids and Comparison of Their Biological Activities
Steroid hormones and triterpenoids belong to the group of physiologically active substances (sex hormones, corticosteroids, etc.) that regulate vital processes in vertebrates and many species of invertebrates and humans [262][263][264][265]. They are regulators of the fundamental vital processes of a multicellular organism-coordinated growth, differentiation, reproduction, adaptation, and behavior [266][267][268]. For more than 90 years, steroid hormones and triterpenoids have been the subject of close attention of chemists since synthetic analogues have long replaced natural steroids and triterpenoids [269][270][271][272][273]. It is known that semi-synthetic or synthetic steroid hormones have properties that steroids do not have, isolated from natural sources. In this section, we present synthetic and semi-synthetic steroids and triterpenoids that contain heteroatoms and do not exist in nature but demonstrate activities that are necessary for pharmacologists and physicians.

Bioactive Epithio Steroids and Triterpenoids
Anabolic steroids are pharmacological drugs that mimic the effect of the male sex hormone testosterone and its derivatives [274][275][276]. Anabolic steroids accelerate the synthesis of protein within cells, which leads to a pronounced hypertrophy of the muscle tissue, because of which, they have found wide application in sports medicine and bodybuilding [277][278][279].
Semi-and/or synthetic epithio steroids represent a rare group of bioactive lipids, since they are hydrophobic molecules insoluble in water, which are not found in nature. Epithio steroids have been reported to possess a variety of cytotoxic activities, and they are widely used as anticancer agents. The thiirane group is an important substance and shows some promising biological activities. Steroids containing an epithio group in positions 2 and 3 are anabolic steroids and are widely known and used in sports medicine. Representatives of this group of steroids are of great interest for pharmaceutical chemistry and medicine [280][281][282][283][284][285][286]. The most widely known are such epithio steroids that are used in sports pharmacology and medicine: epistane (108, 2α,3α-epithio-17α-methyl-5αandrostan-17β-ol), epitiostanol (109, 2α,3α-epithio-5α-androstan-17β-ol), a known potent antiestrogenic and antitumor agent, and hemapolin (110, 2β,3β-epithio-17α-methyl-5αandrostan-17β-ol) [282,283,[287][288][289][290][291]. The chemical structures of epithio steroids are shown in Figure 23 and the biological activities are shown in Table 10. Presented in Figure 24, the anabolic 2α,3α-epithio chlostane (111) shown dominant anticancer activity, and steroid (112) demonstrated dominant properties as an antisecretory agent with 96.7% confidence and acts as an estrogen antagonist with 94.6% confidence.   (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.

Bioactive Selena Steroids
Selenium is an essential metalloid, and it is one of the most necessary trace elements for humans [296]. Selenium occupies an important place in the regulation of metabolism in humans, and therefore, it is necessary to monitor its presence in consumed foods [297,298]. The Allium and Brassica families as well as Brazil nuts, mushrooms (shiitake and white mushrooms), beans, chia seeds, brown rice, sunflower, sesame and flax seeds, and cabbage and spinach contain high enough selenium and organoselenium concentrations [299,300].
There are also many excellent reviews in the literature, which are devoted to the biological role and functions of organoselenium compounds [301][302][303][304]. Apparently, selena steroids are the main group of the essential metalloids that have been synthesized over the past 50 years, and approximately 300 have been synthesized [304][305][306][307][308][309].
The selena steroids numbered 118, 119, 124, 125, 126, and 127 show dominant antihypercholesterolemic activity with a low degree of confidence from 90.5 to 91.2%, although for steroid number 128, the confidence was 95.3%. For another group, the selena steroids numbered 120, 121, 122, and 123, the dominant properties are hyperlipemia, treatment of atherosclerosis, and treatment of lipoprotein disorders with a strong degree of confidence up to 99.6%. The chemical structures of steroids are shown in Figure 25, and the biological activity is shown in Table 11. Figure 26 shows the 3D graph the predicted and calculated biological activity of the selena steroids numbered 120, 121, and 122 with dominant properties as hyperlipemia and treatment of atherosclerosis.

Bioactive Tellura Steroids
Tellura steroids are a rare group of organic synthetic compounds whose biological activity is of great interest for medicine, pharmacology, and the pharmaceutical industry [304,306,308,309,311]. The chemical structures of steroids and triterpenoids are shown in Figure 27, and the biological activity is shown in Table 12.  We found only four tellura steroids, which exhibit properties as regulators of lipid metabolism, dominated by antihypercholesterolemic activity. However, the most interesting from the point of view of pharmacological values is tellura steroid with number 129. In addition to its antihypercholesterolemic activity, it is worth pointing out that this steroid has also been shown to be used as an agent for the treatment of neurodegenerative diseases Alzheimer's and Parkinson's with strong confidence, over 94 percent. The 3D graph demonstrating the predicted and calculated biological activity of the tellura steroid (129) is shown in Figure 28. 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.

Bioactive Astatosteroids
Astatine is natural radioelement that has short-lived isotopes, and synthetic organic astatine compounds are commonly used for radiotherapy [312][313][314]. Steroids containing astatine, which are called astatosteroids, were first synthesized approximately 40 years ago [315]. Some astatosteroids (2-and 4-astatoestradiol and 6-At-cholesterol, 135, 136, and 137) have been synthesized in high radiochemical yields by the reaction of 211 At/I 2 and the corresponding chloromercury compounds. The stability in vitro was determined under different conditions in comparison with the analogous iodo compounds [313]. More recently, 6-astatomethyl-19-norcholest-5(10)-en-3β-ol (134) was synthesized at a yield of 60-70% [316]. The biological activity of these compounds has not been determined. The predicted biological activity of astatosteroids is presented in Table 13. The most characteristic biological properties for these steroids were antineoplastic, antiseborrheic, antisecretoric, and antihypercholesterolemic activities. The chemical structures of steroids are shown in Figure 29 and the biological activity is shown in Table 13. For all astatosteroids shown in Figure 29, antihypercholesterolemic activity is dominated. In addition, all steroids of this group, as shown by PASS, have properties as a treatment for bone diseases. This is a rare property for steroids. Figure 30 shows the 3D graph the predicted and calculated biological activity of the astatosteroid (133).   . 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.

Conclusions
This review focuses on the intriguing topic of lipid metabolism regulation. The literature does not fully describe the means that regulate lipid metabolism. Steroids and triterpenoids presented in this review are of great interest for medicine, and some of them may be potential regulators of lipid metabolism. However, experimental work is required to confirm this thesis. In the world in general, and in North America in particular, the study of biological activities using computer programs is gaining popularity. This is due to the fact that the number of isolated natural and synthetic compounds has long exceeded 20 million; there is no technical possibility of determining biological activity experimentally. Using the PASS program for the last fifteen years has shown that we are on the right track. During this time, we have investigated over 10,000 compounds and identified their potential biological activities. Based on early studies, we have selected a group of steroids and triterpenoids that are presented in this review and correspond to the name of the topic, as potential regulators of lipid metabolism.
Funding: This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgments:
The author is grateful to Anne Kathrin Bendt (Life Sciences Institute, National University of Singapore, Singapore) who initiated this review, and grateful to Tatyana A. Gloriozova (Institute of Biomedical Chemistry, Moscow, Russia) for prompt help in determining the biological activity of the steroids and triterpenoids presented in the article.

Conflicts of Interest:
The author declares that he has no known competing financial interests or personal relationships that could affect the work described in this article.