Rational drug design on the example of light cannabinoids

Rational drug design on the example of light cannabinoids. The drug design has several branches of development, such as irrational selection, rational search and newer layering, computer subtraction, biological mapping of biological objects, simulation of the target and the drug. One way or another, the share of rational search and human intellectual activity in the process of developing the design of preparations is, as before, great. Biomolecular mapping and mathematical models are not able to replace the accumulated experience in the design, and as a result, the drug design develops new theoretical methods. One of these methods is to regulate the activity and strength of the drug, through the use of radicals with more or less complementary interaction forces. The degree of conformity of the chemical compound drug and the target is measured by several quantities: This is the geometric correspondence of the placement of the necessary chemical radicals. This is a quantitative match and a qualitative match. As well as compliance with the degree of mobility, the dynamic behavior of the molecule. Regulation of the activity of a substance is an important parameter that allows you to create drugs with convenient dosage or high safety. To achieve high safety performance, a method of reducing the energy of the bond between the drug and the target is used. This approach makes it possible to establish a low ceiling of maximum activity. Even in case of overdose. these drugs show low activity, which eliminates the development of critical side effects. This method, one way or another, is used in the development of most drugs, but is particularly relevant in the development of centrally active drugs. The molecular mechanism of this approach simulates small concentrations of natural endogenous substances and this happens as follows: A molecule with reduced binding energy by binding to the target gives a signal corresponding to the endogenous hormone, but this signal is weaker. Because such a chemical molecule is not able to be strongly fixed on the target, in the dynamics this process looks as if the target attacked the native hormone in a small concentration. Innervation of the synapse occurs, but it is reduced, even with high concentrations of the drug, because it is not able to give a strong signal in principle. Drug radicals do not have a large "stickiness", they cannot group around themselves the tissue of the receptor, the receptor at a certain moment unloads kinematically, envelops the drug, but quickly returns to its original, not active, position. This process is not related to the concentration of the drug, it is related to the design of the drug. Also, the size of the drug can have a similar role, if the activity of a substance is considered as a dynamic process: A drug with a core that is much smaller than a native mediator, a hormone.., can imitate a mediator... Moving in the active zone of the target and alternately attracting complementary points, performing a complex movement, it contributes to the kinematic receptor unloading, the target gives a signal and relaxes, some time passes and everything repeats again. Or the signal is generated permanently, but has a low level due to the fact that the substance is not able to consolidate all the complementary points of the target in a consolidated manner. In any case, we get the nature of the signal close to the low concentration of the native agent. Separately, it is worth noting the necessary balance of complementary points, a strongly complementary radical can provoke a high activity of the drug. When developing weak drugs, with a low ceiling of activity, the radicals should have a weak "stickiness", the core should not be massive and "sticky". Complementarity should be evenly reduced, or it should be reduced in the critical area. As a rule, this is the area that determines the key signal or the signal of the agonist/antagonist. The features of these specific points are determined by the nature of the receptor and substrate, the precursors of substances from which the native active substance is synthesized and the decomposition products of this substance. These are logical guidelines for virtually any type of target. The substrate recognition scheme is associated with substances of a similar nature that are in the body. Thus, nature makes the target selective and does not allow a false signal from specific intermediate metabolites inside the body. And it can be a source of information or assumptions about that, what can be an antagonist and what should be an agonist. There is a higher selectivity, it is dictated by the fact that for some endogenous hormones there are many receptors in different parts and organs of the body. In the process of evolution, these receptors have changed, but they continue to sorb the same hormone. This makes it possible to influence only our chosen receptor. Such targets have a number of spatial differences and assume selectivity dictated by these spatial differences. Substances that have certain spatial interference can be sorbed by one type of receptor, but cannot be sorbed by another type of receptor. That is why cardiac selective drugs have a molecular mass much more than adrenaline. Adrenaline is not a selective agonist for these targets. A small antagonist would be a nonselective antagonist. But a molecule with a large mass and spatial noise at the right points becomes a selective antagonist or selective antagonist, since the active zone of the receptor has a different landscape. Places for adrenaline on the target surface are greater than the magnitude of the adrenaline itself. Although this space is rocky, it also suggests additional places for sorption. And this makes it possible for such maneuvers, and even possible to enhance the complementary attraction, because the more areas for "sticking" the stronger the signal. And it is possible that in this way it is possible to develop drugs that will be even more active than even natural neurotransmitters or hormones (if necessary). For example, in the case of anti-cancer cannabinoids, the shock activity of cannabinoids in relation to the target may be useful. And in the case of non-narcotic cannabinoids, this therapy can be quite painless. Thus, even without accurate mapping, using a non-rational and rational design drug, many preparations with specified parameters were obtained. And can be obtained in the future using more detailed techniques. This work is devoted to light cannabinoids as a likely promising and new matter for drug design. Some mistakes have been made in the development of synthetic cannabinoids: this is a large molecular weight and does not correspond to the geometric parameters, in favor of simple chemical synthesis. Some well-known chemical molecules of synthetic cannabinoids have the inclusion of pro-opioid radicals (piperidine). This is the reason why the black market of modern synthetic cannabinoids is so dangerous. Also, the pharmacological use of cannabinoids has unresolved shortcomings, this is a high activity of cannabinoids and even marijuana with a large amount of cannabidiol. This creates problems when using cannabinoids in pharmacology, pediatrics.. This complicates the use of cannabinoids, because it repels the state apparatus from the use of marijuana or cannabinoids. The market for cannabinoids, marijuana, is growing and, accordingly, there is a growing need for understanding the mechanisms for developing highly safe drugs. Opinions of the average man divided, from approval to rejection. From the opinion that medical marijuana is a harmless and the best medicine from the list of cannabinoids and other drugs, because it is a natural medicine... And to alertness, because cannabinoids have side effects and are difficult to integrate into pharmacological practice. Society does not have objective data and does not have the best examples for analysis, there is also little data. Let's broaden our horizons a bit before considering a drug design cannabinoids: I want to destroy two myths. The first myth: Marijuana is a plant material and it is the safest. The second myth: there are no light synthetic drugs, all chemistry is heavy and dangerous. 1. Chloroacetic acid is also a natural product, although it looks more like chemical weapons. Butolotoxin is a natural product but it is the most toxic agent. On our Planet Earth lives one percent of the entire diversity of species that was before. Some plants have survived until now, such as gingko biloba. This plant gave amber, but also high-quality nootropic. There were many such plants, perhaps some of synthetic drugs are natural, but we do not guess it. We also know that there are probably millions of planets in the world on which there are oceans. And what plants are likely to grow on these planets. It looks like a reality, and probably natural substances are millions of times more than we think now. 2. Among plant cannabinoids there are lighter than THC, it is carriofillen, but it is not very suitable for use. Synthetic cannabinoids have a non-quality drug design. This is done in favor of the growth of chemical synthesis. Also among synthetic cannabinoids are those that have piperidine in the composition of the molecule. This is dangerous, such drugs have a pro-opioid tendency and can be deadly, much more than lowquality cannabinoids. Synthetic cannabinoids can be of high quality and very light, not powerful, even with increased dosage: Imagine the THC receptor, this is a kind of landscape, ready to take Anandamide. It does not work as a lock and key, it is more difficult. If you have a substance that simulates Anandamide, but in a weaker manifestation, with weaker radicals, a weaker pull energy, a weak complementary force of attraction. And even if they are much smaller than the original, anyway, they will open this door, but the momentum will be weak, even if you take a lot of this substance. And this approach mimics the low level of Anandamide. Even if you take a lot of this substance, it will not be able to give a strong signal level. Such substances are characterized by a low ceiling of activity and weak manifestations of action. This is a biomolecular mechanism that allows us to give mankind safer drugs, even safer than marijuana. Well, now we see that the boundary between synthetic matter and natural is practically erased, and the issue of reliability is reduced to the quality of the design of synthetic matter, or how much nature has endowed us, how much those plants that we have correspond to our goals. And if your goal is to develop easy and safe cannabinoid for pharmacology, pediatrics, psychiatry, and even for recreational purposes and legalization. In this case, we need to work not only on varieties of relatively safe medical marijuana, but also to radically change the qualitative properties of the drugs. Centrally active drugs, opioids, cannabinoids, stimulants, dopimenergics, this is the most difficult matter for the development of drugs, because the quality requirements of centrally active drugs are much higher and their much more. Therefore, many methods and strategies are likely to be used for the development of light cannabinoids. The methods mentioned above, specific strategies for the use of radicals and nuclei, the principles of behavior are shown in the illustration. In the illustration you can see both the radicals with low "stickiness" and the light nuclei, and a small mass of molecules, as well as the use of lactones and internal salts. All these steps contribute to a not high ceiling of activity and weak activity, even in large doses. And it is possible that a record of a high lethal dose of THC will be broken. And getting high, hallucinogenic doses will be impossible. Design examples: As can be seen in the figure, the amide group (anandamide) is replaced by a ketone or dimethyl, which reduces the "stickiness" and increases biostability. Also, at the same time, small core, not pronounced simulation of ethanolamide. Since such substances include pharmakinetics, bioavailability, half-life, catabolism, the design also includes elements of biostability and catabolism, water-soluble metabolites, nonactive metabolites.. As much as possible, more detailed similar qualities are checked during the development of the drug, preclinical studies and clinical research. Clinical and post-clinical studies eliminate nonqualitative effects and provide fine-tuned, specialized drugs for specific uses.