Crystals with more than one molecule in the asymmetric unit (Z ' > 1) present a longstanding challenge for understanding the balance between molecular conformation, intermolecular interactions, and crystal stability. This work reports a detailed investigation of a 3-((3,3-dinitroazetidin-1-yl)diazenyl)-5-(trifluoromethyl)-1H-1,2,4-triazole that crystallizes in the triclinic space group P-1 with two Z ' = 2. The two molecules are formally enantiomers differing in the inversion of the azetidine nitrogen atom and exhibit distinct orientations of the nitro groups, yet they display remarkably similar molecular volumes and Hirshfeld surface characteristics. Using a combination of periodic DFT calculations, topological analysis within the Quantum Theory of Atoms in Molecules, and energy decomposition via the Interacting Quantum Atoms method, we examine the structural and energetic differences between the two independent molecules. The analysis reveals that the similarity in volumetric properties arises from a compensation between electronic deformation and electrostatic stabilization, rather than from geometric identity. The results highlight the role of the triazole and azetidine fragments in determining the energetic balance, while the nitro groups contribute mainly to the rigidity of the crystal packing. This case study provides deeper insight into the Z ' = 2 phenomenon and demonstrates the value of real-space electronic structure methods for unraveling compensation mechanisms in molecular crystals.

Based on the models of predicted crystal packings of salts for nitro and trinitro-substituted tetrazoles using the author's approach of lattice energy mixing, their formation enthalpies were obtained.

Numerous public databases now collect and disseminate biological activity data from literature and patents, forming the basis for chemogenomics and novel scoring functions. However, data quality is often compromised due to multiple citations of values across different studies with varying protocols. To address this issue, we used the XGBoost model in combination with a BERT-based NLP approach and a distance-based out-of-distribution (OOD) data detection method to enhance classification accuracy and exclude review articles.

The review gives a retrospective of methods for molecular modeling of the structures, mechanisms of chemical reactions, and properties of organic compounds. The development and advancement of the ideology of preliminary modeling of the structures and formation mechanisms of reaction products in the planning of any synthesis is a relevant task in this field of science. Some results of the practical application of this paradigm are considered.

A key goal of organic chemistry is to develop new principles for the control of reactions, which can be used to create promising materials demanded in all fields of scientific research and industry. This review is an overview of the scientific advances, which have been made by the N. D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences in the past decade within the framework of current trends in organic chemistry. The review covers the results, which are significant for fundamental research and hold great promise for the application in different areas, from the production of materials, petrochemistry, and chemical ecology to medicine, agriculture, and food industry.

Using quantum chemistry and atom–atom potential methods, the molecular and crystal structures of cubane 1 and all types of unsubstituted azacubanes 2–22 were calculated. Alternative possible polymorphs of cubane 1 have been proposed. The thermochemical properties of azacubanes in the gas and solid phases were assessed. Thermodynamic aspects of stability are considered, and a significant decrease in stability is revealed upon transition from cubane 1 to octaazacubane 22. It has been shown that the density and energetic properties of azacubanes depend nonlinearly on the number of nitrogen atoms in the structure and the density of octaazacubane 22 at room temperature is 1.546 g cm−3, which is significantly lower than the previously given estimate. In this work, DFT calculations were conducted through the software Gaussian 09 using B3LYP functional with basis set aug-cc-PVDZ and the Grimme dispersion correction D2. For crystal structure optimization, the atom–atom potential methods with PMC (packing of molecules in crystal) program were used. Charges for molecular electrostatic potential were fitted by FitMEP, and enthalpies of formation in gas phase were assessed by G3B3.

The rational design of cyclin-dependent protein kinase (CDK) inhibitors presumes the development of approaches for accurate prediction of selectivity and the activity of small molecular weight anticancer drug candidates. Aiming at attenuation of general toxicity of low selectivity compounds, we herein explored the new chemotype of imidazole-4-N-acetamide substituted derivatives of the pan-CDK inhibitor PHA-793887. Newly synthesized compounds 1-4 containing an aliphatic methyl group or aromatic radicals at the periphery of the scaffold were analyzed for the prediction of relative free energies of binding to CDK1, -2, -5, and -9 using a protocol based on non-equilibrium (NEQ) thermodynamics. This methodology allows for the demonstration of a good correlation between the calculated parameters of interaction of 1-4 with individual targets and the values of inhibitory potencies in in vitro kinase assays. We provide evidence in support of NEQ thermodynamics as a time sparing, precise, and productive approach for generating chemical inhibitors of clinically relevant anticancer targets.

Here we propose an over-the-hood docking method that compensates for systematic errors in the docking force fields. This method explicitly estimates the interaction energy of the ligand with the protein surface and uses it as a baseline to estimate the actual binding energy in the active site. It improves the accuracy of virtual screening in the LeadFinder package by up to 48%.

The review aims to present a classification and applicability analysis of methods for preliminary molecular modelling for targeted organic, catalytic and biocatalytic synthesis. The following three main approaches are considered as a primary classification of the methods: modelling of the target – ligand coordination without structural information on both the target and the resulting complex; calculations based on experimentally obtained structural information about the target; and dynamic simulation of the target – ligand complex and the reaction mechanism with calculation of the free energy of the reaction. The review is meant for synthetic chemists to be used as a guide for building an algorithm for preliminary modelling and synthesis of structures with specified properties. The bibliography includes 353 references.

The review summarizes the publications, available at the time it was written, addressing the chemical and biological processes that occur in the human body upon exposure to coronaviruses, in particular SARS-CoV-2. The mechanisms of viral particle entry into the cell, viral replication and impact on the immune system and on oxygen transport system are considered. The causes behind complications of the viral infection, such as vasculitis, thrombosis, cytokine storm and lung fibrosis, are discussed. The latest research in the field of small molecule medications to counteract the virus is surveyed. Molecular targets and possible vectors to exploit them are considered. The review is primarily written for specialists who want to understand the chains of activation, replication, action and inhibition of SARS-CoV-2. Due to the short period of such studies, the data on complexes of small molecule compounds with possible protein targets are not numerous, but they will be useful in the search and synthesis of new potentially effective drugs. The bibliography includes 144 references.

Although CDK7 inhibitors are considered to be potential anticancer drugs, all inhibitors developed so far have significant disadvantages preventing their further use. We have developed a new CDK7 inhibitor scaffold lacking hepatotoxicity using molecular dynamics (MD) and free energy perturbation (FEP/MD) methods, and were able to double its binding affinity after additional research. The combination of MD and FEP/MD methods was shown to be a valuable instrument for the development of novel and potent CDK7 inhibitors for anticancer therapy.

The ability of monomethoxy-substituted o-diphenylisoxazoles 2a-d to interact with the colchicine site of tubulin was predicted using computational modeling, docking studies, and calculation of binding affinity. The respective molecules were synthesized in high yields by three steps reaction using easily available benzaldehydes, acetophenones, and arylnitromethanes as starting material. The calculated antitubulin effect was confirmed in vivo in a sea urchin embryo model. Compounds 2a and 2c showed high antimitotic microtubule destabilizing activity compared to that of CA4. Isoxazole 2a also exhibited significant cytotoxicity against human cancer cells in NCI60 screen. For the first time, isoxazole-linked CA4 derivatives 2a and 2c with only one methoxy substituent were identified as potent antimitotic microtubule destabilizing agents. These molecules could be considered as promising structures for further optimization.

Identification of disulfiram and neratinib as putative covalent inhibitors of SARS-CoV-2 virus main protease Mpro by a combination of ‘on-top docking’ procedure, expert evaluation of potential hits and molecular dynamics is reported herein. This finding shows the importance of further development of virtual screening add-ons.

The rapid development of new machine learning techniques led to significant progress in the area of computer-aided drug design. However, despite the enormous predictive power of new methods, they lack explainability and are often used as black boxes. The most important decisions in drug discovery are still made by human experts who rely on intuitions and simplified representation of the field. We used D3R Grand Challenge 4 to model contributions of human experts during the prediction of the structure of protein–ligand complexes, and prediction of binding affinities for series of ligands in the context of absence or abundance of experimental data. We demonstrated that human decisions have a series of biases: a tendency to focus on easily identifiable protein–ligand interactions such as hydrogen bonds, and neglect for a more distributed and complex electrostatic interactions and solvation effects. While these biases still allow human experts to compete with blind algorithms in some areas, the underutilization of the information leads to significantly worse performance in data-rich tasks such as binding affinity prediction.

The hydrogenation of diphenylacetylene (DPA) on palladium–silver catalysts with a single-atom structure was investigated. It has been shown experimentally that the reaction rate of alkene to alkane hydrogenation is substantially lower than the rate of DPA semi-hydrogenation. The kinetic barriers of all stages of hydrogenation were calculated by the DFT method.

The Diels-Alder reaction is a cornerstone of modern organic synthesis. Despite this, it remains essentially inaccessible to biosynthetic approaches. Only a few natural enzymes catalyze even a formal [4 + 2] cycloaddition, and it remains uncertain if any of them proceed via the Diels-Alder mechanism. In this study, we focus on the [4 + 2] cycloaddition step in the biosynthesis of spinosyn A, a reaction catalyzed by SpnF enzyme, one of the most promising "true Diels-Alderase" candidates. The four currently proposed mechanisms (including the Diels-Alder one) for this reaction in water (as a first-order approximation of the enzymatic reaction) are evaluated by an exhaustive quantum mechanical search for possible transition states (728 were found in total). We find that the line between the recently proposed bis-pericyclic [J. Am. Chem. Soc. 2016, 138 (11), 3631] and Diels-Alder routes is blurred, and favorable transition states of both types may coexist. Application of the Curtin-Hammett principle, however, reveals that the bis-pericyclic mechanism accounts for ∼83% of the reaction flow in water, while the classical Diels-Alder mechanism contributes only ∼17%. The current findings provide a route for modeling this reaction inside the SpnF active site and inferring the catalytic architecture of possible Diels-Alderases.

A combination of the common quantum mechanics based transition state theory and exhaustive conformational search for the modeling of difficult reactions with hundreds of competing transition states is proposed. This approach is applied to study all transition state conformations of a reaction occurring in the catechol O-methyltransferase (COMT) active site in the absence of a major part of the enzyme, and the results are compared to the recent QM/MM modeling of this reaction within the enzyme. The main points of the method are (i) constraining of forming bonds upon conformer generation and (ii) preliminary constrained optimizations of located conformations to minima using a quantum mechanical method. Importantly, this methodology is applicable to the quantum mechanical part in QM/MM calculations and can reduce demand for large sampling in difficult cases.

Free energy perturbation (FEP)-based molecular modeling simulation of 5-fluoropyrimidine and 1,3,5-triazine derivatives followed by their synthesis and experimental evaluation have been carried out to estimate kinase selectivity profile. 5-Fluoropyrimidine derivatives show similar binding affinity for c-Src, Btk and Jak1 kinases, while 1,3,5-triazine derivatives demonstrate c-Src kinase selectivity.