Molecular Docking Research Articles

Integrated systems pharmacology, molecular docking, and MD simulations investigation elucidating the therapeutic mechanisms of BHD in Alzheimer’s disease treatment

Integrated systems pharmacology, molecular docking, and MD simulations investigation elucidating the therapeutic mechanisms of BHD in Alzheimer’s disease treatment

Exploring the Molecular Interaction Between NR2E3 and NR1D1 in Retinitis Pigmentosa: A Docking and Molecular Dynamics Study

ABSTRACTBackground and AimsRetinitis pigmentosa (RP) is a hereditary retinal disorder that gradually leads to vision loss due to photoreceptor cell degeneration. This study aims to investigate the clinical features and genetic underpinnings of RP within a large Iranian family. Our focus centered on mutations in the NR2E3 gene, which plays a critical role in the development and maintenance of the retina.MethodsTwenty‐five family members showed symptoms of RP, and fourteen of them underwent clinical examinations conducted by geneticists and ophthalmologists. The DNA samples of five individuals diagnosed with RP from the family were subjected to whole‐exome sequencing (WES) as part of the study. The candidate variant identified through WES was subsequently confirmed using bidirectional sequencing in additional family members. Additionally, in silico analysis, including molecular modeling, protein–protein docking, and molecular dynamics simulation (MD), was employed to assess potential pathogenic effects associated with the candidate variants.ResultsOphthalmic examination revealed night blindness, which is a common symptom among affected individuals. Genetic analysis identified a homozygous missense variant (c.934G>A/p.R311Q) in NR2E3 exon 6, which co‐segregates with other affected family members. Furthermore, molecular docking analysis indicated potential disruption in the binding affinity between NR2E3 and NR1D1 proteins. In‐depth, molecular dynamics analysis, considering parameters such as RMSD, RMSF, and hydrogen bonding, revealed notable differences between normal and mutant protein complexes.ConclusionExploring the molecular interaction between NR2E3 and NR1D1 provides new insights into the pathogenic mechanism of the p.R311Q mutation in RP.

Chemical profile, biological activities, and molecular docking of Algerian Juniperus phoenicea berries

The chemical composition, antioxidant activities, and α-amylase enzyme inhibitory activity of Algerian Juniperus phoenicea L berries were quantitatively and qualitatively determined in this study. Essential oil (EO) and non-polar crude extracts from cyclohexane and ethyl acetate were prepared, and the chemical profile was determined using GC-MS technique. The predominant compound in the EO was α-pinene (76.03%), while communic acid (23.66% and 22.38%) was the main compound in both non-polar crude extracts. The antioxidant potential of the samples was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,20-azino-bis(3-ethylbenzothiazoline-6-sulfonicacid)-diammonium salt (ABTS), and phenanthroline. All samples showed weak antioxidant capacity. The antidiabetic effect was assessed in vitro using the α-amylase assay; a strong inhibitory effect against the α-amylase enzyme was detected for both cyclohexane and ethyl acetate extracts with IC50 (IC50 = 186.91 ± 5.74 mg/mL and IC50 = 351.48 ± 0.17 mg/mL, respectively). Finally, an in silico study was performed for both α-amylase and α-glucosidase proteins to enhance our outcomes.

A Machine Learning‐Based Approach for the Prediction of Anticoagulant Activity of Hypericum perforatum L. and Evaluation of Compound Activity

ABSTRACTIntroductionHypericum perforatum L. (HPL) is extensively researched domestically and internationally as a medicinal plant. However, no reports of studies related to the anticoagulant activity of HPL have been retrieved. The specific bioactive components are unknown.ObjectiveThe aim of this study was to develop a machine learning (ML) method for rapid prediction of anticoagulant activity in HPL and evaluation of compound activity. Materials and methods.First, an in vitro anticoagulant activity assay was developed for the determination of the bioactivity of various medicinal parts of HPL. Then, the peak areas of compounds in HPL were integrated using UPLC‐Q‐TOF‐MS analysis. Subsequently, nine independent ML methods and two ensemble learning methods have been established to predict the anticoagulant activity of HPL and to evaluate the contribution of compounds. Feature importance scores were used for models visualization.ResultsA total of 24 compounds were shown to exhibited superior anticoagulant activity. Molecular docking experiments likewise confirmed this result. The results show that the branches of HPL have excellent anticoagulant activity, which has been previously overlooked. The established ML model demonstrated good performance in the prediction of the activity of HPL.ConclusionThe results were accurate and reliable, which significantly improved the efficiency of active compounds screening, and further exploration in this area is warranted.

Bioinformatics analysis to design a multi-epitope mRNA vaccine againstS. agalactiaeexploiting pathogenic proteins.

Antibiotic resistance in bacterial pathogen infections is a growing global issue that occurs due to their adaptation to changing environmental conditions. Therefore, producing an efficient vaccine as an alternative approach can improve the immune system, eradicate related pathogens, and overcome this growing problem.Streptococcus agalactiaebelongs to group B Streptococcus (GBS). Colonization of GBS during pregnancy is a significant risk factor for infants and young children. S. agalactiae infected population exhibits resistance to beta-lactams, including penicillin and the second-line antibiotics erythromycin and clindamycin.On the other hand, there are currently no commercial vaccines against this pathogen. Vaccination of pregnant women is a highly effective method to protect newborns and infants from S. agalactiaeinfection, and it has been identified as an urgent demand by the World Health Organization. This study employed various immunoinformatic tools to develop an effective vaccine that could trigger both humoral and cell-mediated immunity and prevent disease. For this purpose, three conserved antigenic proteins of the main pathogenic strains ofS. agalactiaewere utilized to predict CTL, HTL, and B-cell epitopes for producing an mRNA vaccine against different strains ofS. agalactiae. The selected epitopes were fused using proper linkers. The Resuscitation promoting factor E (RpfE) sequence was incorporated in the designed vaccine construct as an adjuvant to boost its immune response. Different physicochemical characteristics of the final designed vaccine, modeling of the three-dimensional structure, molecular docking, molecular dynamics simulation, and immunological response simulation were screened following vaccine administration in an in vivo model.Computational immune simulation data identified that IgG1, IgM, INF γ, IL-2, T helper, and B-cell populations increased significantly after vaccination. These findings suggested that the vaccine candidate may provide good protection againstS. agalactiaeinfection. However,experimental and animal model studies are required for additional validation and implementation in human vaccination programs.

Exploring the Antiviral Potential of Artemisia annua Through JAK-STAT Pathway Targeting: A Network Pharmacology Approach

Background: Artemisia annua, a plant with antiviral potential, has shown promise against various viral infections, yet its mechanisms of action are not fully understood. This study explores A. annua’s antiviral effects using network pharmacology and molecular docking, focusing on key active compounds and their interactions with viral protein targets, particularly within the JAK-STAT signaling pathway—a critical mediator of immune responses to viral infections. Methods: From the TCMSP database, we identified eight active compounds and 335 drug targets for A. annua, with 19 intersecting targets between A. annua compounds and viral proteins. A protein–protein interaction (PPI) network highlighted 10 key hub genes, analyzed further through Gene Ontology (GO) and KEGG pathways to understand their immune and antiviral roles. ADMET properties of the active compound Patuletin (MOL004112) were assessed, followed by 200 ns molecular dynamics simulations to examine its stability in complex with JAK2. Results: PPI analysis identified JAK2, MAPK3, MAPK1, JAK1, PTPN1, HSPA8, TYK2, RAF1, MAPT, and HMOX1 as key hub genes, with JAK2 emerging as a critical regulator of immune and antiviral pathways. ADMET analysis confirmed Patuletin’s favorable pharmacokinetic properties, and molecular dynamics simulations showed a stable Patuletin-JAK2 complex, with FEL analysis indicating minimal disruption to JAK2’s intrinsic flexibility. Conclusions: These findings highlight JAK2 as a promising target in the antiviral activity of A. annua compounds, particularly Patuletin, supporting its potential as an antiviral agent and providing a foundation for further research on A. annua’s therapeutic applications.

Bioinformatics combined with network pharmacology and experimental validation to identify key biomarkers of hepatocellular carcinoma and corresponding compounds in Radix Astragali and Pueraria Mirifica.

The occurrence and death rates of primary hepatocellular carcinoma (HCC) are increasing, and there remains a shortage of effective oral medications with minimal side effects. We aim to identify potential biomarkers and compounds from Radix Astragali (RA) and Pueraria Mirifica (PM) to treat liver cancer and improve prognosis. Differentially expressed genes (DEGs) associated with HCC were identified by bioinformatics analysis of three datasets, GSE112791, GSE101685, and GSE45114. Using public databases to predict the bioactive components and possible targets of RA and PM. Target crossover from Gene Expression Omnibus (GEO) and public databases were used to identify potential biomarkers for HCC. Subsequently, validation and prognostic value analyses were performed using the Gene Expression Profile Interaction Analysis (GEPIA) platform. The Cytoscape software created a network of "compound targets" to pinpoint compounds linked to the biomarkers. Molecular docking techniques were utilized to validate the connection between these compounds and the identified biomarkers. Ultimately, the HepG2 liver cancer cell line was chosen to assess the inhibitory effect of Hederagenin (HDG) and to confirm the expression of ADH1B through Western blot analysis. In this study, four key biomarkers (NR1I2, ADH1B, NQO1, GHR) were identified. Molecular docking showed that these four core targets could form stable conformations with the corresponding compounds. As the drug concentration decreases, the inhibitory effect on HepG2 diminishes, and the survival rate of HepG2 cells significantly declines following the administration of 100 µmol/L HDG. Compared to the control, the expression of ADH1B protein is significantly increased in HepG2 cells treated with 100 µmol/L HDG. The study identified four key biomarkers (ADH1B, GHR, NQO1, NR1I2) that have prognostic ability for HCC. This study provides biomarkers and potential targeted monomeric medicines for treating HCC.

Synthesis, Biological Activities, and Molecular Docking Studies of 15-Site Matrine Based Isatohydrazone Derivatives as Potential Anticancer Agents.

To acquire matrine derivatives with enhanced anticancer activity, we designed and synthesized twenty-one 15-site matrine based isatohydrazone derivatives were designed and synthesized. The anti-proliferative activity of all the compounds against human cervical cancer cells (HeLa), human colon cancer cells (HCT116), and non-small cell lung cancer cells (A549) was examined by the MTT method. The majority of the compounds exhibited superior anticancer activity compared to matrine. Among them, compound 5a displayed the most potent anti-proliferative activity, with IC50 values of 9.02±0.33 μM (HeLa), 10.49±1.09 μM (HCT116), and 15.23±0.12 μM (A549), respectively. Compound 5a can also induce cell cycle arrest in the G0/G1 phase and trigger apoptosis, as well as inhibit cell clonal formation and migration. Molecular docking experiments have demonstrated that compound 5a can form hydrogen bonds and hydrophobic interactions with EGFR-related protein 7AEI.

High Throughput Screening and Molecular Docking Analysis on DNA Polymerase (Pol) Β Cancer Variant K289M

DNA polymerase (pol) β plays a critical role in DNA repair mechanisms, and mutations in this enzyme have been implicated in various cancers. Because it may play a role in oncogenesis by altering the fidelity of DNA synthesis, the K289M variation of pol β is particularly interesting. This study uses Python molecular graphic, Cavity based docking, SwissDock, Structure validation server among other computational tools to undertake high-throughput screening and molecular docking investigations of DNA pol β cancer variant K289M (PDB ID: 6NKR). Ligands such as Boceprevir, Nirmatrelvir, Ritonavir, Carmofur, and Lopinavir were docked to identify potential inhibitors targeting this variant. Structural validation using the SAVES server and topology analysis using PDBSum helped assess the quality of the protein structure. Our results highlight several binding pockets with strong ligand affinities, suggesting potential therapeutic interventions for targeting pol β K289M in cancer.

Biological control of nosemosis in Apis mellifera L. with Acacia nilotica extract.

Nosemosis is one of the most devastating diseases of Apis mellifera (Honey bees) caused by the single-celled spore-forming fungiNosema apis,N. ceranae and N. neumanii, causing a severe loss on the colony vitality and productivity. Fumagillin, a MetAP2 inhibitor, was a certified treatment for controlling nosemosis, nevertheless, due to its deleterious effects on honey bees and humans, it is prohibited. So, searching for novel biological agents with affordable selectivity to target Nosema species infecting Apis mellifera, with nil toxicity to bees and humans is the main objective of this study. Nosema species were isolated from naturally infected honey bees. The methanolic extracts of Acacia nilotica, Elaeis guineensis, and Catharanthus roseus were tested to selectively control the growth of Nosema spp of honeybees. The spores of Nosema species were molecularly and morphologically identified. Among the tested plant extracts, the methanolic extracts (0.1%) of A. nilotica had the most activity towards Nosema spp causing about 37.8 and 32.5% reduction in the spores' load at 5- and 9-days post-infection, respectively, compared to the untreated control. At 0.1%, the A. nilotica methanolic extract exhibited the highest inhibitory effect for Nosema spores, without any obvious bee mortality. Catharanthus roseus displayed a reduction of spores by 27.02%, with bee mortality rate of 27.02%. At 1% for 5 dpi, the A. nilotica extracts led to 18.18% bee mortality, while the C. roseus extracts resulted in 100% mortality, as revealed from the toxicity and quantification bioassays. So, the extracts of A. nilotica and C. roseus had a significant effect in controlling the N. apis and N. ceranae titer compared to the infected untreated control at both time points. The titer of N. apis and N. ceranae was noticeably decreased by more than 80% and 90%, in response to A. nilotica, compared to the control. From the metabolic profiling by GC-MS analysis, the most frequent active compounds of A. nilotica were 2,4,6-trihy-droxybenzoic acid, 1,2-dihydroxybenzene, myristic acid, and linoleic acid. These compounds were analyzed in silico to assess their binding affinity to the ATP binding protein, methionine aminopeptidase and polar tube protein of Nosema species as target enzymes. The compound 2,4,6-trihydroxybenzoic acid had the lowest energy to bind with ATP binding protein, methionine aminopeptidase and polar tube protein of Nosema, followed by 1,2-dihydroxybenzene and myristic acid, compared to fumagilin. So, from the experimental and molecular docking analysis, the extracts of A. nilotica had the highest activity to attack the cellular growth machinery of Nosema species without an obvious effect to the honeybees, ensuring their prospective promising application.

Potential antiviral activity of rhamnocitrin against influenza virus H3N2 by inhibiting cGAS/STING pathway in vitro.

Influenza remains a serious issue for public health and it's urgent to discover more effected drugs against influenza virus. Rhamnocitrin, as a flavonoid, its effect on influenza virus infection remains poorly explored. In this study, rhamnocitrin showed antiviral effect and anti-apoptosis on influenza virus A/Aichi/2/1968 (H3N2) in MDCK cells and A549 cells. In addition, molecular docking revealed that rhamnocitrin have good binding activity with the target proteins cGAS and STING, molecular dynamic simulation and surface plasmon resonance showed that rhamnocitrin could form a stable complex with the above proteins. Moreover, the qPCR and western blot assays further verified that rhamnocitrin could reduce type I IFN and proinflammatory cytokines production by inhibiting the cGAS/STING pathway. Taken together, the results suggest that rhamnocitrin could be a potential anti-viral agent against influenza.

Novel Tricyclo[4.2.1]Nonane and Bicyclo[2.2.1]Heptane Derivatives: Synthesis, in Vitro Biological Activities and in Silico Studies.

The target benzothiazole derivatives (8a-g) were synthesized starting from norbornene. The addition of dichloroketene to norbornene followed by the reduction of chlorine atoms were synthesized tricyclo[4.2.1.02,5]non-7-en-3-one (4). The condensation of benzaldehyde derivatives with compound 4 were obtained chalcone analogs (6a-g). Finally, benzothiazole derivatives (8a-g) were obtained by the reaction of the chalcone analogs with 2-aminobenzothiol in an acidic medium. The antiproliferative activities of compounds 6a-g and 8a-g were determined against C6 (rat brain tumor) and HeLa (human cervical carcinoma) cell lines using a BrdU cell proliferation ELISA assay with 5-fluorouracil (5-FU) as a standard. In both series, when compared with 5-FU (IC50=3.8 μM for C6 and 16.33 μM for HeLa), the most active compounds against C6 cells were 6a and 8g with IC50 values of 14.13 μM and 29.99 μM, respectively. With this, 6a, 6e, 6f, and 8b were the most active compounds against HeLa cells with IC50 values of 0.8, 1.21, 19.33 and 18.13 μM, respectively. Additionally, the SwissADME online web tool was used to predict the physicochemical and ADME properties of the tested compounds. The results showed that all compounds possess promising predicted physiochemical and pharmacokinetic properties and comply with Lipinski's rule of 5, indicating that they are predicted to be orally bioavailable that they possess a predicted bioavailability score of 0.55. Furthermore, in the SwissADME Boiled-Egg chart, all compounds showed high predicted GIT absorption, while compounds 6a-g showed blood-brain barrier (BBB) permeation, and compounds 8a-g did not. Moreover, none of the compounds was (P-gp) substrates. This study investigated the potential interactions between the antiapoptotic proteins Bcl-2, Bcl-xl, Bcl-w, Brag-1, Bfl-1, and Mcl-1 and compounds 6a, 8b, and 8g through molecular docking studies. The findings suggest that these compounds may effectively inhibit antiapoptotic proteins, as evidenced by significant hydrogen bonds and hydrophobic interactions, particularly with Bcl-xl.

In vitro α-amylase and α-glucosidase inhibitors study of Cymbopogon martinii essential oil and molecular docking study of predominant components, PASS prediction and ADME/Tox studies

In vitro α-amylase and α-glucosidase inhibitors study of Cymbopogon martinii essential oil and molecular docking study of predominant components, PASS prediction and ADME/Tox studies

Bioassay‐Guided Extraction and Isolation of Natural Herbicides from Dried Zanthoxylum limonella Alston Fruits

AbstractWeeds are problematic plant species around the world. Various strategies exist for controlling weeds, but chemical treatment remains the preferred method, particularly when using natural substances. In this research, a crude aqueous‐methanol extract from dried Zanthoxylum limonella fruits was acid‐base partitioned into four fractions: neutral extract (NE), acid extract (AE), basic extract (BE), and aqueous extract (AQ). These fractions were further separated into seventeen subfractions: NEF1 to NEF7, AEF1 to AEF5, and BEF1 to BEF5, which were then tested for herbicidal activity against the growth of Chinese amaranth (Amaranthus tricolor) and barnyard grass (Echinochloa crus‐galli). Active subfractions were isolated via column chromatography and identified using spectroscopic methods, yielding seven active compounds: xanthoxyline (1), tambulin (2), atanine (3), prudomestin (4), skimmianine (5), p‐methoxybenzoic acid (6), and methyl caffeate (7). Compounds 2–7 had not been previously reported in Z. limonella. Xanthoxyline (1) was identified as the most potent botanical herbicide, fully inhibiting seed germination of Chinese amaranth and barnyard grass. This compound also decreased seed imbibition and α‐amylase activity in both species. Molecular docking studies on the α‐amylase enzyme (PDB ID: 1BG9) revealed that the aromatic, hydroxy, and carbonyl groups of xanthoxyline (1) interact with the enzyme's active sites.

Identification of potential mechanisms of Schisandrin B in the treatment of idiopathic pulmonary fibrosis by integrating network pharmacology and experimental validation.

Idiopathic pulmonary fibrosis (IPF) is a worsening fibrotic condition characterized by a short survival rate and limited treatment options. This study evaluates the potential anti-fibrotic properties of Schisandrin B (Sch B) through network pharmacology and experimental validation. A mouse model of bleomycin-induced pulmonary fibrosis was established, and the modeled mice were treated with Sch B at three doses (20 mg/kg/day, 40 mg/kg/day, and 80 mg/kg/day). A fibrotic model was developed in NIH/3T3 cells by treating them with TGF-β (10 ng/mL) and administering Sch B at various concentrations (10, 20, and 40 µM). The results revealed that Sch B treatment delayed the development of bleomycin-induced pulmonary fibrosis and substantially decreased the transcription levels of collagen I and α-SMA in TGF-β-induced fibroblasts. Core targets were screened with protein-protein interaction network analysis, molecular complex detection (MCODE), and CytoHubba plugin. The application of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and molecular docking highlighted the significance of the HIF-1α signaling pathway in the potential mechanism of Sch B in IPF therapy. Western blot, PCR, and immunofluorescence were performed to validate the effects of Sch B on HIF-1α. In vivo and in vitro, Sch B administration reduced HIF-1α expression. These outcomes provide valuable insights into the potential mechanism by which Sch B delays IPF development, with HIF-1α potentially serving as a key target. However, further investigation is warranted to assess the safety and efficacy of Sch B in clinical settings.

Ternary Carbon Spheres/PAA-Al2O3 Nanoparticles as an Efficient Catalyst for RhB Dye Degrader and Bactericidal Agent; Molecular Docking Analysis

Ternary Carbon Spheres/PAA-Al2O3 Nanoparticles as an Efficient Catalyst for RhB Dye Degrader and Bactericidal Agent; Molecular Docking Analysis

Saponins as potential novel NLRP3 inflammasome inhibitors for inflammatory disorders.

Nucleotide-binding domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) is a downstream protein from the pattern recognition receptor family that forms the NLRP3 inflammasome. The NLRP3 inflammasome releases caspase-1, IL-1β, and IL-18, contributing to inflammatory responses associated with diabetes mellitus, arthritis, and ischemia-reperfusion injury. Recent studies suggest that specific saponin monomers and extracts from traditional Chinese medicines can inhibit inflammatory responses and related pathways, including the production of inflammatory factors. MCC950 is one of the most influential and specific NLRP3 inhibitors. Comparative molecular docking studies have identified 22 of the 37 saponin components as more robust binders to NLRP3 than MCC950. Dioscin, polyphyllin H, and saikosaponin-a have the highest binding affinities and potential NLRP3 inhibitors, offering a theoretical basis for developing novel anti-inflammatory therapies.

Eleutheroside B alleviates oxidative stress and neuroinflammation by inhibiting the JAK2/STAT3 signaling pathway in a rat high altitude cerebral edema model

BackgroundHigh altitude cerebral edema (HACE) is a condition where the central nervous system experiences severe impairment as a result of sudden oxygen deprivation at high elevations. At present, effective measures for preventing and treating this condition are still lacking. Eleutheroside B (EB), the primary natural active compound found in the Eleutheroside senticosus, has demonstrated various biological functions. It has also shown significant potential in addressing acute mountain sickness and various neurological disorders. However, additional investigation is required to explore the potential protective effects and its underlying mechanisms of EB on HACE.MethodsThe male rats received pre-treatment with either vehicle, EB 100 mg/kg or 50 mg/kg, Dexamethasone 4 mg/kg, or coumermycin A1 100 μg/kg. To simulate the hypobaric hypoxia environment at a plateau of 6,000 m, a hypobaric hypoxia chamber was utilized. The therapeutic effects of EB were assessed through measurements of brain water content, histopathological observation, and evaluation of oxidative stress and inflammatory factors using immunofluorescence and ELISA. Furthermore, molecular docking, molecular dynamics simulation and Western blot were employed to clarify its molecular mechanism. Through these analyses, the underlying mechanism by which EB on HACE was identified.ResultsPre-treatment with EB demonstrated a significant protective effect against HACE by effectively reducing brain water content, down-regulating HIF-1α and AQP4 protein expression induced by hypoxia and reversing pathological changes in brain tissue and neuron damage. Compared to the group treated with HACE alone, the group pre-treated with EB showed a significant reduction in levels of ROS and MDA, as well as an increase in GSH. In addition, pre-treatment with EB led to a significant decrease in the levels of IL-1β, IL-6, and TNF-α. Molecular docking and dynamics simulations indicated that EB has a strong binding affinity to the JAK2/STAT3 signaling pathway. Western blot further confirmed that EB significantly downregulated the expression of JAK2/STAT3 related proteins in the brain tissue of HACE rats. Additionally, coumermycin A1, an agonist of the JAK2, reversed the anti-oxidative stress and neuroinflammation against HACE of EB.ConclusionEB exerts its antioxidant stress and anti-neuroinflammatory effects by inhibiting the JAK2/STAT3 signaling pathway in a rat HACE model.

Identification of novel PAD2 inhibitors using pharmacophore-based virtual screening, molecular docking, and MD simulation studies.

In the realm of epigenetic regulation, Protein arginine deiminase 2 (PAD2) stands out as a therapeutic target due to its significant role in neurological disorders, rheumatoid arthritis (RA), multiple sclerosis (MS), and various cancers. To date, no in silico studies have focused on PAD2 for lead compound identification. Therefore, we conducted structure-based pharmacophore modeling, virtual screening, molecular docking, molecular dynamics (MD) simulations, and essential dynamics studies using PCA and free energy landscape analyses to identify repurposed drugs and selective inhibitors against PAD2. The best pharmacophore model, 'Pharm_01,' had a selectivity score of 10.485 and an excellent ROC curve quality of 0.972. Pharm1 consisted of three hydrogen bond donors (HBD) and two hydrophobic (Hy) features (DDDHH). A virtual screening of about 9.2million compounds yielded 2575 hits using a fit value threshold of 2.5 and drug-likeness criteria. Molecular docking identified the top ten molecules, which were verified using MD simulations. Stability was verified using MM-PBSA studies, whereas conformational differences were investigated using PCA and free energy landscape analyses. Two hits (Leads 1 and 2) from the DrugBank dataset showed promise for repurposing as PAD2 inhibitors, while one hit compound (Lead 8) from the ZINC database emerged as a novel PAD2 inhibitor. These findings indicate that the discovered compounds may be potent PAD2 inhibitors, necessitating additional preclinical and clinical research to produce viable treatments for cancer and neurological disorders.

Molecular Docking of Endolysins for Studying Peptidoglycan Binding Mechanism

Endolysins of bacteriophages, which degrade the bacterial cell wall peptidoglycan, are applicable in many industries to deal with biofilms and bacterial infections. While multi-domain endolysins have both enzymatically active and cell wall-binding domains, single-domain endolysins consist only of an enzymatically active domain, and their mechanism of peptidoglycan binding remains unexplored, for this is a challenging task experimentally. This research aimed to explore the binding mechanism of endolysins using computational approaches, namely molecular docking and bioinformatical tools, and analyze the performance of these approaches. The docking engine Autodock Vina 1.1.2 and the 3D-RISM module of AmberTools 24 were studied in the current work and used for receptor–ligand affinity and binding energy calculations, respectively. Two possible mechanisms of single-domain endolysin–ligand binding were predicted by Autodock Vina and verified by the 3D-RISM. As a result, the previously obtained experimental results on peptidoglycan binding of the isolated gamma phage endolysin PlyG enzymatically active domain were supported by molecular docking. Both methods predicted that single-domain endolysins are able to bind peptidoglycan, with Autodock Vina being able to give accurate numerical estimates of protein–ligand affinities and 3D-RISM providing comparative values.