Current Medicinal Chemistry - Volume 27, Issue 1, 2020

Several studies report the effects of excessive use of sugars and sweeteners in the diet. These include obesity, cardiac diseases, diabetes, and even lymphomas, leukemias, cancers of the bladder and brain, chronic fatigue syndrome, Parkinson's disease, Alzheimer's disease, multiple sclerosis, autism, and systemic lupus. On the other hand, each sugar and sweetener has a distinct metabolic assimilation process, and its chemical structure plays an important role in this process. Several scientific papers present the biological effects of the sugars and sweeteners in relation to their chemical structure. One important issue dealing with the sugars is the degree of similarity in their structures, focusing mostly on optical isomerism. Finding and developing new sugars and sweeteners with desired properties is an emerging research area, in which in silico approaches play an important role.

Orphan drug products (e.g. drugs and biologics) in the United States are those that treat people with rare chronic diseases, often cancer or metabolic disease. The rare disease condition being treated by these orphan drugs must serve a patient population of less than 200,000 people in the U.S. in order to earn the orphan drug product title. Just as the disease conditions are seen as “orphans,” so, we assert is the thermochemical understanding of the drugs themselves in terms of the chemical structures that define those drugs. This article illustrates this orphan thermochemical status for a recent series of orphan drugs.

Background: In view of many current mosquito-borne diseases there is a need for the design of novel repellents. Objective: The objective of this article is to review the results of the researches carried out by the authors in the computer-assisted design of novel mosquito repellents. Methods: Two methods in the computational design of repellents have been discussed: a) Quantitative Structure Activity Relationship (QSAR) studies from a set of repellents structurally related to DEET using computed mathematical descriptors, and b) Pharmacophore based modeling for design and discovery of novel repellent compounds including virtual screening of compound databases and synthesis of novel analogues. Results: Effective QSARs could be developed using mathematical structural descriptors. The pharmacophore based method is an effective tool for the discovery of new repellent molecules. Conclusion: Results reviewed in this article show that both QSAR and pharmacophore based methods can be used to design novel repellent molecules.

In the context of reconsidering the Quantitative Structure-Activity Relationship (QSAR) methods at the economical level, namely the optimization rules of OECD, the present review unfolds the key features of Minimal Sterical, Monte-Carlo and Minimal Topological Difference (MTD) methods, developed for quantitative treatment of the relations between biological activity of organic chemical compounds (drugs, pesticides, and so on) and their structures. The initial Minimal Steric Difference (MSD) is completed by the three-dimensional variant of the MTD method, being the last one referred to here, while the main principles of validating and guiding a viable QSAR method verified by the analytical-automated MTD, thus enlarging the perspectives of understanding the chemical-biological interaction at the level of ligand-receptor sites, cavity, and walls, with a true service to the future adaptive molecular design.

Pesticides are used today on a planetary-wide scale. The rising need for substances with this biological activity due to an increasing consumption of agricultural and animal products and to the development of urban areas makes the chemical industry to constantly investigate new molecules or to improve the physicochemical characteristics, increase the biological activities and improve the toxicity profiles of the already known ones. Molecular databases are increasingly accessible for in vitro and in vivo bioavailability studies. In this context, structure-activity studies, by their in silico - in cerebro methods, are used to precede in vitro and in vivo studies in plants and experimental animals because they can indicate trends by statistical methods or biological activity models expressed as mathematical equations or graphical correlations, so a direction of study can be developed or another can be abandoned, saving financial resources, time and laboratory animals. Following this line of research the present paper reviews the Structure-Activity Relationship (SAR) studies and proposes a correlation between a topological connectivity index and the biological activity or toxicity made as a result of a study performed on 11 molecules of organophosphate compounds, randomly chosen, with a basic structure including a Phosphorus atom double bounded to an Oxygen atom or to a Sulfur one and having three other simple covalent bonds with two alkoxy (-methoxy or -ethoxy) groups and to another functional group different from the alkoxy groups. The molecules were packed on a cubic structure consisting of three adjacent cubes, respecting a principle of topological efficiency, that of occupying a minimal space in that cubic structure, a method that was called the Clef Method. The central topological index selected for correlation was the Wiener index, since it was possible this way to discuss different adjacencies between the nodes in the graphs corresponding to the organophosphate compounds molecules packed on the cubic structure; accordingly, "three dimensional" variants of these connectivity indices could be considered and further used for studying the qualitative-quantitative relationships for the specific molecule-enzyme interaction complexes, including correlation between the Wiener weights (nodal specific contributions to the total Wiener index of the molecular graph) and the biochemical reactivity of some of the atoms. Finally, when passing from SAR to Q(uantitative)-SAR studies, especially by the present advanced method of the cubic molecule (Clef Method) and its good assessment of the (neuro)toxicity of the studied molecules and of their inhibitory effect on the target enzyme - acetylcholinesterase, it can be seen that a predictability of the toxicity and activity of different analogue compounds can be ensured, facilitating the in vivo experiments or improving the usage of pesticides.

Background: Synthetic compounds with pharmaceutical applications in brain disorders are daily designed and synthesized, with well first effects but also seldom severe side effects. This imposes the search for alternative therapies based on the pharmaceutical potentials of natural compounds. The natural compounds isolated from various plants and arthropods venom are well known for their antimicrobial (antibacterial, antiviral) and antiinflammatory activities, but more studies are needed for a better understanding of their structural and pharmacological features with new therapeutic applications. Objectives: Here we present some structural and pharmaceutical features of natural compounds isolated from plants and arthropods venom relevant for their efficiency and potency in brain disorders. We present the polytherapeutic effects of natural compounds belonging to terpenes (limonene), monoterpenoids (1,8-cineole) and stilbenes (resveratrol), as well as natural peptides (apamin, mastoparan and melittin). Methods: Various experimental and in silico methods are presented with special attention on bioinformatics (natural compounds database, artificial neural network) and cheminformatics (QSAR, drug design, computational mutagenesis, molecular docking). Results: In the present paper we reviewed: (i) recent studies regarding the pharmacological potential of natural compounds in the brain; (ii) the most useful databases containing molecular and functional features of natural compounds; and (iii) the most important molecular descriptors of natural compounds in comparison with a few synthetic compounds. Conclusion: Our paper indicates that natural compounds are a real alternative for nervous system therapy and represents a helpful tool for the future papers focused on the study of the natural compounds.

We revisit, in the key of structural chemistry, one of the most known and important drugs: the aspirin. Although apparently simple, the factors determining the molecular structure and supramolecular association in crystals are not trivial. We addressed the problem from experimental and theoretical sides, considering issues from X-ray measurements and results of first-principle reconstruction of molecule and lattices by ab initio calculations. Some puzzling problems can give headaches to specialists and intrigue the general public. Thus, the reported polymorphism of aspirin is disputed, a so-called form II being alleged as a result of misinterpretation. At the same time, were presented evidences that the structure of common form I can be disrupted by domains where the regular packing is changed to the pattern of form II. The problems appear even at the level of independent molecule: the most stable conformation computed by various techniques of electronic structure differs from those encountered in crystals. Because the energy difference between the related conformational isomers (computed as most stable vs. the experimental structure) is small, about 1 kcal/mol, comprised in the error bars of used methods, the unresting question is whether the modelling is imprecise, or the supramolecular factors are mutating the conformational preferences. By a detective following of the issue, the intermolecular effects were made responsible for the conformation of the molecule in crystal. The presented problems were gathered from literature results, debates, glued with modelling and analysis redone by ourselves, in order to secure the unitary view of the considered prototypic topic.

In the present work, recent data on the sources, occurrence and fate of human-use pharmaceutical active compounds (PhACs) in the aquatic environment have been reviewed. Since PhACs and their metabolites are usually present as mixtures in the environment at very low concentrations, a particular emphasis was placed onto the PhACs mixtures, as well as on their short-term and long-term effects against human and environmental health. Moreover, a general overview of the main conventional as well as of the latest trends in wastewaters decontaminant technologies was outlined. Advantages and disadvantages of current processes were also pointed out. It appears that numerous gaps still exist in the current knowledge related to this field of interest, and further studies should be conducted at the global level in order to ensure a more efficient monitorisation of the presence of PhACs and their metabolites into the aquatic environment and to develop new mitigation measures.

Lack of specificity and subsequent therapeutic effectiveness of antimicrobial and antitumoral drugs is a common difficulty in therapy. The aim of this study is to investigate, both by experimental and computational methods, the antitumoral and antimicrobial properties of a series of synthesized imidazole-pyridine derivatives. Interaction with three targets was discussed: Dickerson-Drew dodecamer (PDB id 2ADU), G-quadruplex DNA string (PDB id 2F8U) and DNA strain in complex with dioxygenase (PDB id 3S5A). Docking energies were computed and represented graphically. On them, a QSAR model was developed in order to further investigate the structure-activity relationship. Results showed that synthesized compounds have antitumoral and antimicrobial properties. Computational results agreed with the experimental data.