. Станом на 2020 рік 1,0 млрд людей у світі досягли віку 60 років або більше та процес старіння населення світу продовжується. Згідно з прогнозами до 2030 року ця цифра зросте до 1,4 млрд, тобто літньою буде кожна шоста людина. До 2050 року кількість осіб у віці 60 років і старше подвоїться та складатиме 2,1
млрд. Збільшується також чисельність людей старечого віку. Очікується, що з 2020 до 2050 року кількість світового населення у віці 80 років і старше потроїться та дорівнюватиме 426 млн (WHO, 2023). З огляду на такі демографічні тенденції ВООЗ розробила Глобальну стратегію та план дій щодо старіння та здоров'я
(WHO, 2017). Для досягнення найкращих результатів щодо загального здоров’я, якості життя (ЯЖ), забезпечення автономії літньої людини використовується підхід всебічного геріатричного оцінювання, що передбачає реалізацію індивідуальних діагностичних та лікувально-відновлювальних програм
мультидисциплінарною командою (Єна Л.М., Христофорова Г.М., 2022). Внесок фармацевта у такий багатопрофільний процес може здійснюватися шляхом надання фармацевтичної опіки (ФО) (The Pharmacist Guide to Implementing Pharmaceutical Care, 2019). Корекція застосування лікарських засобів (ЛЗ) не
впливає на показники смертності літніх пацієнтів, однак може зменшити кількість звернень за екстреною допомогою та забезпечити позитивний вплив на ЯЖ (Настанова Duodecim: Перегляд режиму терапії ЛЗ у пацієнтів похилого віку, 2017). Тож, серед завдань, що стоять перед фармацевтом при наданні ФО
геріатричним пацієнтам уникнення застосування потенційно недоцільних ліків, стримування поліфармації / поліпрагмазії, попередження проявів побічних реакцій (ПР) на ЛЗ, забезпечення коректного дозування ліків тощо.
Computer-aided rational drug design encompasses the identification of potential biological targets for drug candidates followed by an intensive search ensues to find a drug-like small molecules that can modulate the function of the identified macromolecule resulting in a therapeutic effect. This approach becomes possible due to the availability of information about the three-dimensional chemical structures of ligands and biomolecules. Thus, to be efficient, computer-aided drug design (CADD) techniques including both ligand- and structure-based, must be accurate with the structural data manipulation as the knowledge of macromolecules and ligands structures as well as unbound and receptor-bound conformations is the precondition of the vital importance for the application of 3D computational molecular modeling approaches.
The aim of the current work was to analyze, systematize and summarize the recent literature data discussing conformational ensembles of small organic molecules, the main approaches and techniques applied for their generation and the conformational sampling of drug-like molecules significance in modern computer-aided drug design.
Three-dimensional spatial arrangements of atoms that organic molecules can adopt are known as conformations, their diversity is ensured by rotational bonds, changes in bond lengths, bond angles and torsions, interconversion between different conformations can be achieved by rotations about formally single bonds. Thus, a set of stable spatial geometric structures of a molecule with the constant connectivity matrix constitutes the set of its conformations. In their turn, conformational ensembles are represented by the sets of equilibrium conformations existing under certain thermodynamic conditions in defined environmental medium. Consequently, thorough conformational analysis is critically important in many areas of research, such as drug discovery, protein engineering, and the design of catalysts.
Conformer generation leading to exploring and sampling the low energy conformational space of drug-like molecules continues to be a relevant task focusing on ligands structure pre-organization with the aim to minimize energetic penalties associated with undesired flexibility, sub-optimal arrangement of functional groups interacting with the protein binding site or unwanted internal stabilization.
Drug-like molecules can adopt a great number of conformations depending on the amount of rotatable bonds, angels and torsions flexibility and the rigidity properties of their rings and cycles. It was shown that even the solid-state ligands bounded to corresponding biotargets can possess conformational diversity. Structural data drawn from the Protein Data Bank (PDB) revealed that the same ligand precented in at least two different protein−ligand structures may be found in multiple conformations which differed significantly (RMSD > 2 Å) [1]. This means that a small molecule must adopt the bioactive conformation that is the conformation which can be recognized by the receptor and produce the biological response. Bioactive conformations construction for flexible small organic molecules is challenging and complex problem in modern drug design reasoned by the large number of degrees of freedom even for relatively small ligands.
Development of an effective and safe antioxidant compound is still challenging in the last few decades. There has been an increasing interest in the role of reactive oxygen species (ROS) in food, drugs, and even living system. Free radical formation is associated with the normal natural metabolism of aerobic cells. They are inevitably exposed to reactive oxygen species formed as oxygen metabolites. Oxidative stress which is largely characterized by reactive oxygen and nitrogen species is implicated in the development of a number of chronic and degenerative diseases such as atherosclerosis, cancer, cirrhosis, diabetes, wound healing and aging. Free radicals are highly reactive and therefore can attack membrane lipids, generating carbon radicals and peroxy radicals, which cause lipid peroxidation. Therefore, scientists in various disciplines have become more interested in naturally-occurring antioxidants as well as in related synthetic derivatives that could provide active components which prevent or reduce the impact of oxidative stress. Іn order to study the effect of various substituents in the molecules on the nature of thepharmacological activity of thiazolo[4,5-b]pyridin-2-ones, a series of new compounds were synthesized based on the previously obtained 5,7-dimethyl-3Hthiazolo[4,5-b]pyridin-2-one. The high electrophilicity of the N3 position in 5,7-dimethyl-3H-thiazolo[4,5-b]pyridin- 2-one allows to use of its functionalization as a convenient method for obtaining various N3-substituted derivatives to expand the range of thiazolo[4,5-b]pyridines. In particular, an NH center with a mobile hydrogen atom at the N3 position in 5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-2-one allows conducting a synthesis based on 3-substituted derivatives. This conversion was carried out through the stage of obtaining potassium salt. Several chloroacetamides were tested as alkylating agents, which allowed to obtain the corresponding 2-(5,7-dimethyl-2-oxo-thiazolo[4,5-b]pyridin-3-yl)-N-aryl-acetamides (1–6). Methods of quantitative elemental analysis, mass spectrometry, and 1H NMR spectroscopy were used to confirm the structure and individuality of the synthesized substances. Interpretation of the spectra revealed that the signals for protons of all structural units were observed in their characteristic ranges.