Kharkiv University Bulletin. Chemical Series

Benchmarking Google DeepMind’s AlphaFold 3 Performance for Protein 3D-Structure Prediction

Yelyzaveta Duma — 2024-09-11

The 3D structure of proteins is directly linked to their function, making its determination crucial for understanding biological processes and addressing issues related to human health and life sciences. Despite the continuous experimental acquisition of new protein structures, there remains a significant gap between the number of protein sequences available and those that have an established experimental high-resolution tertiary structure. Several computational approaches have focused on predicting protein structures using either templates or empirical force field modeling. In recent years, various methods have been combined to address the individual limitations of these approaches, leading to the development of AlphaFold 3 (AF3) by Google DeepMind. AF3 enables prediction of 3D protein structures with high accuracy based on its amino acid sequence. In this study, we benchmarked applicability, performance, and limitations of AF3 for predicting 3D structure of a broad series of proteins, including SARS-CoV-2 coronavirus proteins, other bacterial and viral proteins, as well as some plant enzymes. We found that AlphaFold 3 could capture the overall backbone features of the most examined proteins in terms of small deviation from available X-ray structures. Some minor miss-folding of N- and C-terminal segments were common, which, often, did not affect biological roles of the studied proteins. In cases involving protein dimers or higher-order oligomers, there are notable differences between the predicted AF3 models of a single-chain monomer and their corresponding experimental structures. These discrepancies are particularly evident in regions related to protein dimerization, assembly, and binding interfaces. Ultimately, while capturing the overall fold, predicting the complex structure of the Spike glycoprotein is still beyond the current capabilities of AF3.

Evolutionary Structure Optimization of Ensitrelvir as Non-Covalent Inhibitor of SARS-CoV-2 Main Protease Mpro

Kateryna Lohachova — 2024-09-27

Ensitrelvir is a non-covalent, non-peptide inhibitor of the SARS-CoV-2 main protease, M^pro. It has demonstrated effective antiviral activity against various coronavirus variants in vitro, along with favorable drug metabolism and pharmacokinetic profiles suitable for oral treatment. Thus, developing novel analogues of ensitrelvir is of great importance. In this study, we conducted in silico design of its analogues by employing evolutionary structure optimization of the parent ensitrelvir scaffold. In the first stage, we generated a virtual evolutionary library consisting of 6334 new analogues based on a series of fitness criteria, including molecular weight (M_w), cLogP, polar surface area, structural and conformational similarity, flexibility, and molecular shape. Next, we filtered the evolutionary library using a 3D pharmacophore model created from the available X-ray structure of the co-crystallized complex of ensitrelvir and M^pro. We then performed molecular docking calculations to rank the selected candidates according to their binding affinity and selectivity for the M^pro receptor. This binding score ranking allowed us to identify ten analogues of ensitrelvir that exhibit superior binding affinity to the protease M^pro compared to the original ensitrelvir inhibitor. Our evolutionary structure optimization indicates that the primary structural modifications that enhance the overall antiviral effect of ensitrelvir are found in the 1-methyl-1H-1,2,4-triazole and 6-chloro-2-methyl-2H-indazole fragments.

Structure and Transport Properties of NaPF6 Solutions in Mixtures of Ethylene Carbonate with Dimethyl Carbonate for Sodium-Ion Batteries: MD Simulation

Anastasiia Borovyk — 2024-10-03

Sodium-ion batteries (SIBs) have the potential to become new efficient electrical energy storage devices. However, at the moment, the main problem is the lack of a clear technology for their production. For the industrial production of SIBs, it is necessary to develop cathode and anode materials, as well as to choose the optimal composition of the electrolyte. For this purpose, using molecular dynamics modeling methods, we calculated the density, viscosity, electrical conductivity, and diffusion coefficients for NaPF₆ systems in the binary solvent EC:DMC (15:85 wt%, 30:70 wt%, and 50:50 wt%), and their structural properties were also considered.

The structure of the solvation shell of cations and anions was studied within the framework of radial distribution functions and current coordination numbers. The results indicate a more structured solvation shell of Na⁺ cations than of PF₆^- anions.

The study of transport properties showed that the most suitable electrolytes for the production of sodium-ion batteries are systems in which EC:DMC=15:85 wt%. This is due to the fact that the electrolyte of this particular composition showed the lowest viscosity values in the region of all concentrations, as well as the highest values of electrical conductivity. The Na⁺ diffusion coefficients for this system also reach the highest values compared to electrolytes of other compositions, which is a convincing argument for its future use in sodium-ion batteries.

Methods of Protection/Deprotection of Hydroxy Groups in the Synthesis of Polyhydroxy Flavonols

Oleksii Demidov — 2024-10-29

The article represents a review of methods for obtaining polyhydroxy flavonols without protection of hydroxy groups, as well as syntheses using methylation, alkylation and benzylation of the initial reagents and, accordingly, demethylation, dealkylation and debenzylation of the final flavonols. It is shown that the most convenient for the synthesis of natural polyhydroxy flavonols and their analogues is the debenzylation reaction using a
Pd/C catalyst in tetrahydrofuran, which allows to obtain flavonols containing both hydroxy and methoxy groups. Syntheses using benzylation/debenzylation reactions are easily scaled up, which allows to obtain of large quantities of polyhydroxy flavonols, in addition, the latter do not contain impurities of hydrogen halides, which makes it possible to use the obtained flavonols in the pharmaceutical and food industries.

The syntheses of hydroxy flavonols with a pyrogallol-like structure of the side phenyl ring were carried out, and the natural flavonol fisetin, a promising medicinal product and component of food additives, was obtained through benzylation/debenzylation reactions. effect of ensitrelvir are found in the 1-methyl-1H-1,2,4-triazole and 6-chloro-2-methyl-2H-indazole fragments.

Synthesis of Mono- and Diphenyl Substituted Salicylic Aldehydes, Important Building Blocks for the Synthesis of Fluorescent Dyes and Dyes-Sensitizers for DSSC

Pavlo Trostianko — 2024-11-06

Salicylic aldehydes are of interest for the synthesis of many biologically active compounds, ligands, fluorescent probes and functional dyes-sensitizers for DSSCs, etc.

In this work, we have developed a method for the synthesis of mono- and diphenyl substituted salicylic aldehydes by the Suzuki-Miyaura cross-coupling reaction of the corresponding bromosalicylaldehydes with phenylboronic acid, in order to study the possibilities of modifying the structure of functional dyes. A series of experiments were performed on the variation of synthesis conditions, replacement of solvents and catalysts both under conditions of convection heating at atmospheric pressure and using a conductive heating reactor with a sealed vessel Anton Paar Monowave 50.

In the process of searching for optimal reaction conditions, great attention was paid to the modern requirements of "green chemistry". The best result was obtained by carrying out the Suzuki-Miyaura cross-coupling reaction of bromosalicylaldehydes with phenylboronic acid in water using the Pd(PPh₃)₄ catalyst. This method was improved by using 10% Pd/C as a catalyst, which has a number of advantages, namely: greater availability, ease of storage and use, lower cost and environmental safety. Also, the 10% Pd/C catalyst is more resistant to environmental influences, which allowed the reactions to be carried out without the use of an inert atmosphere in a conductive heating reactor with a sealed tank Anton Paar Monowave 50.