Foreword

From the very beginning, the principle and purpose of medicine, in particular of pharmacology, was a struggle with natural selection for human life and health. Using natural sources, even ancient physicians were able to save patients suffering from infections of bacterial, viral, parasitic, or fungal origin, who would otherwise become severely ill or even die without treatment. Among these preparations, materials from ants and bees, scorpions and flies, snakes and frogs, as well as sponges, mushrooms, fishes, and mammals were used for centuries with more or less success. But of course, different plants, trees, and herbs, their seeds, fruits, roots, leaves, and flowers contained the most of ancient therapeutic remedies. The development of rational synthetic chemistry, starting from the 19th century, allowed to broaden the panel of compounds and to substitute compounds isolated from natural sources with those synthesized in laboratories. Since that time, owing to combinatory chemistry, desired structures and scaffolds, including those not occurring in nature, could be synthesized and used as potential drugs. The development and application of cell-free systems for high throughput screening of chemical libraries against specific targets resulted in a dramatic acceleration of drug-oriented researches. Finally, the modern computational methods of molecular modeling and virtual screening, including methods using artificial intelligence, allowed to test in silico virtual libraries consisting of hundreds of millions of compounds. Despite the wide possibilities the synthetic chemistry and rational drug design offer, it must be always taken into account that all potential drugs are supposed to be applied for the treatment of human beings. This imposes specific restrictions and sets certain requirements for their scaffolds. Indeed, enzymes of eukaryotic cells have specific preferences for the isomeric composition of compounds. One of such examples is that our ribosomes can handle only with L-, but not D-stereoisomers of amino acids to produce functional proteins. Many other synthetic scaffolds cannot be utilized by cellular enzymatic systems either. Not surprising are, therefore, the results of the study of Newman and Cragg (2020) having demonstrated that among all therapeutic agents approved from 1981 to 2019, only one-third of them was of fully synthetic origin. Other two-thirds were either completely natural or modified natural structures (i.e., those derived from a natural product with semisynthetic modification) as well as compounds made by total synthesis, but whose pharmacophore was from a natural product. These compounds, including fully natural ones, are now successfully used in both Western medicine and ethnical pharmacological systems, such as Ayurveda, traditional Chinese medicine, and many others. Secondary plant metabolites are, therefore, an inexhaustible source for new scaffolds having, with high probability, a potential biological activity. Of great importance and highest novelty and variability are the plants of poorly studied regions of rainforests in Asia, Africa, and South America. Among infectious organisms, viruses represent an important group of causative agents of diseases that are extremely hard to fight. Due to a specific life cycle, viral components disseminate within the cell after infection, and for some period, virus becomes a part of the cell. Therapeutic compounds, therefore, must be very selective and tightly discriminate viral and cellular components to kill a virus without affecting the cell. Moreover, on the battlefield among viruses and humans, one can see in real time the process of selection of viruses that are resistant to antiviral drugs. This problem is important for such dangerous pathogens as the human immunodeficiency virus, herpesviruses, influenza viruses, and many others. For some drugs and viruses, the genetic barrier for resistance is high, but in other cases, it is very low, so that viruses can overcome the inhibiting activity of a drug. This becomes especially actual when patients do not adhere to doses and regimens of drug use, thus providing a sub-therapeutical concentration of a drug in the body. As an example, treatment of human immunodeficiency virus infection with a single drug results in an easy selection of resistant variants and progression of disease despite the therapy. However, the introduction of the second and third drug into the scheme of treatment leads to the effective elimination of the virus, because the development of double- and triple-resistant viral mutants is much less probable.