Dmitry Nilov

Poly(ADP-ribose)polymerase 1 (PARP1) is an enzyme that interacts with chromatin during DNA repair and transcription processes; the molecular mechanisms of these processes remain to be determined. Previously, we have shown that PARP1 can bind to and reorganize nucleosomes using two modes of interaction with a mono-nucleosome, which are realized through PARP1 binding to the ends of linker DNA and to the nucleosome core. Here, it is shown that the latter mode of binding induces the reorganization of nucleosome structure and is more stable under the conditions of poly(ADP-ribosyl)ation (PARylation). The initial nucleosome structure is fully recovered after the dissociation of autoPARylated PARP1. The competition between PARP1 and linker histone H1.0 for binding to a nucleosome is mediated by the PARP1-H1.0 interaction and is affected by the length of linker DNA fragments. Longer linkers stabilize H1.0-nucleosome complexes, while shorter linkers facilitate displacement of H1.0 from the chromatosome by PARP1. PARylation removes both H1.0 and PARP1 from the complexes with nucleosomes. The data suggest that the H1.0 displacement from chromatin by PARP1 that is likely modulated by the density of nucleosomes might reduce chromatin compaction and facilitate access of PARP1-dependent DNA repair and transcription factors to nucleosome and inter-nucleosomal DNA.

Virtual screening (VS) has become a widely used tool in drug discovery, enabling the identification of potential drug candidates from large compound libraries. However, the success of VS heavily relies on the accuracy and efficiency of the approaches used. There are several challenges that need to be addressed to improve the performance of VS, including (Muegge et al., 2024).1. Scoring functions: Scoring functions, mathematical algorithms predicting ligand-protein binding affinity, remain imperfect with limitations in accuracy and high false positive rates.for target binding, such as those that are too large, too small, or contain undesirable functional groups.3. Prediction of physicochemical properties/pharmacological activity: Beyond binding affinity, predicting the physicochemical and pharmacological properties of VS-identified compounds, such as solubility, permeability, metabolism, and toxicity, is crucial.Virtual screening involves screening vast compound libraries, potentially containing millions or billions of compounds, which poses significant computational challenges for data management and analysis.Experimental validation of virtual screening results, while crucial for confirming binding affinity and activity, is often expensive and time-consuming.Therefore, developing more efficient validation methods remains an important challenge.Overcoming these challenges is essential to improving the performance of virtual screening and accelerating the discovery of new drugs (Oliveira et al., 2023). This Research Topic showcases recent advancements and innovative strategies for refining virtual screening effectiveness in drug discovery. It comprises seven original research papers describing advanced docking and post-docking approaches (DFT, molecular dynamics, and MM-PBSA) for effectively selecting active ligands with desired properties.The challenges and possible solutions mentioned above can be verified in the study conducted by Elsaman et al. that demonstrates a computational screen of 460,000 compounds from the National Cancer Institute library to identified KHK-C inhibitors using pharmacophorebased virtual screening, a multi-step approach prioritized compounds with strong binding affinity, favorable pharmacokinetic profiles, and high efficacy to find inhibitors of ketohexokinase C (KHK-C) a key enzyme in fructose metabolism, a promising therapeutic strategy to combat diseases like obesity and diabetes caused by high fructose intake. This efficient, cost-effective in silico approach selected the compound 2 is a promising KHK-C inhibitor with favorable predicted pharmacokinetics and toxicity, suggesting its potential as a treatment for fructose-driven metabolic disorders and meriting further study.Another approach driven by Zhang et al. underscores the importance of natural product chiisanoside isolated from Acanthopanax sessiliflorus as valuable source for developing targeted therapies against cisplatin-induced ototoxicity hearing loss, a widespread issue affecting communication and quality of life over 5% of the global population. A. sessiliflorus, consumed for over a century in some regions, has shown potential against cisplatin-induced ototoxicity (CIO).This study screened 26 chiisanoside derivatives, and found that compound 19 significantly protected against CIO damage. In this way, using pharmacophore-based virtual screening, researchers discovered that compound 19 can prevent ototoxicity, finding a novel approach for treating hearing loss. Since the emergence of SARS-CoV-2, highly transmissible variants have driven interest in drug repurposing, particularly antimalarials. For this purpose, Quijada et al. conducted in vitro assays in two host mammalian cell systems, Vero-E6 and Calu-3 cells to assess the antiviral activity of the 26 antimalarial and antiviral compounds against the Delta and A2.5 variants isolated in Panama (2020Panama ( -2022)). In Vero-E6 cells, chloroquine significantly inhibited the Delta variant, while amodiaquine, artemisone, and ivermectin were active against the A2.5 variant. In Calu-3 cells, chloroquine, amodiaquine, artesunate, lumefantrine, and hydroxychloroquine were effective against the Delta variant, whereas only amodiaquine and arteether showed activity against the A2.5 variant, demonstrating variant-and cell-type-dependent responses. This study highlights the importance of choosing relevant cell models for SARS-CoV-2 research, as drug efficacy differs based on viral variant and host cell type.Malaria, caused by Plasmodium parasites and transmitted by Anopheles mosquitoes, remains a significant global health threat. Despite continuous efforts to develop safer and more effective medications, the disease poses major challenges for new drug discovery. The most dangerous species, P. falciparum, degrades hemoglobin and is developing increasing drug resistance, highlighting the urgent need for new therapeutic targets. Aspartyl proteases like plasmepsin X, which is crucial for the parasite's survival by digesting hemoglobin, are promising targets for new antimalarial drugs. A recent study by Pathak and Kim (2025) used a fragment-based virtual screening approach to identify potential inhibitors. Starting with a library of over 14,000 compounds, they systematically narrowed the candidates down to 20 priority compounds that with ran molecular dynamics (MD) simulations identified compounds 3 and 4 as superior inhibitors, offering new therapeutic possibilities against drug-resistant malaria.Ultimately, this work contributes new insights and therapeutic possibilities in the ongoing battle against drug-resistant malaria.Computational assay was used for identifying millet-derived compounds that antagonize the interaction between bisphenols and estrogen-related receptor gamma. The exposure of bisphenol A and its analogs on humans through oral, transdermal, and respiratory routes is associated with reproductive, developmental, metabolic, and carcinogenic...

Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2) play an important role in DNA damage repair in cells, and their inhibition is used for the treatment

7-Methylguanine (7-MG) is a natural inhibitor of poly(ADP-ribose) polymerase 1 and tRNA-guanine transglycosylase, the enzymatic activity of which is central for the proliferation of cancer cells. Recently, a number of preclinical tests have demonstrated the safety of 7-MG and a regimen of intragastric administration was established in mice. In the present work, the pharmacological activity of 7-MG was studied in BALB/c and BALB/c nude mice with transplanted tumors. It was found that 7-MG effectively penetrates tumor tissue and suppresses colon adenocarcinoma growth in the Akatol model, as well as in a xenograft model with human HCT116 cells.

Poly(ADP-ribose) polymerase 1 (PARP1) plays a major role in the DNA damage repair and transcriptional regulation, and is targeted by a number of clinical inhibitors. Despite this, catalytic mechanism of PARP1 remains largely underexplored because of the complex substrate/product structure. Using molecular modeling and metadynamics simulations we have described in detail elongation of poly(ADP-ribose) chain in the PARP1 active site. It was shown that elongation reaction proceeds via the S _N 1-like mechanism involving formation of the intermediate furanosyl oxocarbenium ion. Intriguingly, nucleophilic 2′ _A -OH group of the acceptor substrate can be activated by the general base Glu988 not directly but through the proton relay system including the adjacent 3′ _A -OH group.

Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2) play an important role in repairing DNA, and their inhibition is being used to treat certain oncological diseases. New inhibitors of PARP are being actively developed and the mechanisms of their action are being studied. In the present work, using the inhibitors talazoparib, olaparib and veliparib, as example, it is shown that electrophoresis of DNA complexes with PARP1 and PARP2 in polyacrylamide gel in the presence of inhibitors makes it possible to identify the effect of inhibitors on the affinity of enzymes to DNA, and after adding the NAD+ substrate, to evaluate the inhibition of the catalytic activity of enzymes. When selecting new inhibitors for biomedical research, it is important to consider these mechanisms of action against PARP1 and PARP2.

As a result of the computer screening of a library of sulfo-substituted compounds, molecules capable of binding to the active site of transketolase from Mycobacterium tuberculosis were identified. An experimental verification of the inhibitory activity of the most promising compound, STK045765, against a highly purified recombinant enzyme preparation was carried out. It was shown that the STK045765 molecule competes for the binding site of the pyrophosphate group of the thiamine diphosphate cofactor and, at micromolar concentrations, is able to suppress the activity of mycobacterial transketolase. The discovered furansulfonate scaffold may serve as the basis for the creation of anti-tuberculosis drugs.

Inhibitors of human poly(ADP-ribose) polymerase (PARP) are considered as promising agents for the treatment of cardiovascular, neurological, and other diseases accompanied by inflammation and oxidative stress. Previously, the ability of the natural compounds 7-methylguanine (7mGua) and 8-hydroxy-7-methylguanine (8h7mGua) to suppress the activity of the recombinant PARP protein was demonstrated. In the present work, we have investigated the possibility of PARP-inhibitory and cytoprotective action of 7mGua and 8h7mGua against rat cardiomyoblast cultures (undifferentiated and differentiated H9c2). It was found that 7mGua and 8h7mGua rapidly penetrate into cells and effectively suppress H2O2-stimulated PARP activation (IC50 = 270 and 55 µM, respectively). The pronounced cytoprotective effects of 7mGua and 8h7mGua were shown in a cellular model of oxidative stress, and 8h7mGua exceeded the classic PARP inhibitor 3-aminobenzamide for effectiveness. The obtained data indicate the prospects for the development of PARP inhibitors based on guanine derivatives and their testing on models of ischemia-reperfusion tissue damage.

Inhibitors of human poly(ADP-ribose) polymerase (PARP) are considered as promising agents for treatment of cardiovascular, neurological, and other diseases accompanied by inflammation and oxidative stress. Previously, the ability of natural compounds 7-methylguanine (7mGua) and 8-hydroxy-7-methylguanine (8h7mGua) to suppress activity of the recombinant PARP protein was demonstrated. In the present work, we have investigated the possibility of PARP-inhibitory and cytoprotective action of 7mGua and 8h7mGua against the rat cardiomyoblast cultures (undifferentiated and differentiated H9c2). It was found that 7mGua and 8h7mGua rapidly penetrate into the cells and effectively suppress the H₂O₂-stimulated PARP activation (IC₅₀ = 270 and 55 μM, respectively). The pronounced cytoprotective effects of 7mGua and 8h7mGua were shown in a cellular model of oxidative stress, and effectiveness of 8h7mGua exceeded the classic PARP inhibitor 3-aminobenzamide. The obtained data indicate promise for the development of PARP inhibitors based on guanine derivatives and their testing using the models of ischemia–reperfusion tissue damage.

Apoptosis is a type of programmed cell death that eliminates damaged cells and controls the development and tissue homeostasis of multicellular organisms. Caspases, a family of cysteine proteases, play a key role in apoptosis initiation and execution. The maturation of caspases and their activity is fine-tuned by post-translational modifications in a highly dynamic fashion. To assess the effect of post-translational changes, potential sites are routinely mutated with residues persistent to any modifications. For example, the serine residue is replaced with alanine or aspartic acid. However, such substitutions could alter the caspase active site's conformation, leading to disturbances in catalytic activity and cellular functions. Moreover, mutations of other amino acid residues located in critical positions could also break the structure and functions of caspases and lead to apoptosis perturbation. To avoid the difficulties of employing mutated residues, molecular modeling approaches can be readily applied to estimate the potential effect of amino acid substitutions on caspase structure. The present protocol allows the modeling of both the wild-type caspase and its mutant forms with the biomolecular simulation package (Amber) and supercomputer facilities to test the effect of mutations on the protein structure and function.