In silico pharmacology最新文献

Cancer remains a major global health challenge and is the second leading cause of mortality worldwide. Despite extensive efforts, the development of effective cancer therapies is still limited. Mitogen-activated protein kinase 7 (MAPK7), a critical regulator of cell proliferation, gene transcription, and metabolism, has recently emerged as a promising therapeutic target for cancer intervention. In this study, we applied advanced machine learning-based computational approaches to identify potential MAPK7 inhibitors. Virtual screening of a large library of drug-like molecules using machine learning models identified 33 active compounds against MAPK7. Molecular docking further refined these hits to five compounds with favorable binding affinities and strong interactions with key catalytic residues. Molecular dynamics (MD) simulations provided additional insights into the stability and conformational dynamics of protein-ligand complexes, highlighting amino acid residues crucial for inhibitor retention within the active site. Collectively, our findings suggest that these five compounds represent promising MAPK7 inhibitors, offering new opportunities for the development of targeted cancer therapeutics. To the best of our knowledge, this is the first study to combine machine learning-based virtual screening, molecular docking, and MD simulations for the identification of MAPK7 inhibitors.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00531-1.

In early tumorigenesis, TGF-β acts as a tumour suppressor by inhibiting cell growth and inducing apoptosis, thereby maintaining cellular homeostasis and preventing malignant transformation. During cancer progression, however, TGF-β signalling is hijacked to promote tumour growth, invasion, migration, and immune evasion, contributing to stemness acquisition and drug resistance. This dual role highlights its context-dependent nature and therapeutic relevance in advanced cancers. In the present study, berberine derivatives were designed and evaluated computationally for their interactions with TGF-β receptors. Ligand and protein preparation were followed by molecular docking and molecular dynamics simulations. Docking analyses revealed that all derivatives exhibited improved binding scores compared to the parent berberine molecule, with all berberine derivatives demonstrating the strongest predicted affinity for both TGFβRI and TGFβRII over the parent molecule. Molecular dynamics simulations, assessed through RMSD, RMSF, SASA, Rg, and PCA analyses, confirmed that the receptor-ligand complexes remained stable throughout the trajectories, supporting their potential to modulate TGF-β signalling. These findings suggest that structural modification of berberine may enhance receptor binding and provide a rational framework for further experimental validation. Considering the limited oral bioavailability of berberine, the development of optimised derivative molecules may overcome this drawback and improve therapeutic potential in the management of advanced cancers.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00512-4.

The herb Nelumbo nucifera G., popularly known as ' lotus,' is well known in ancient texts for various kidney and urine formation conditions. The present study aimed to assess the effect of Nelumbo nucifera flower extract on the formation of kidney stones and evaluate the potential mechanisms involved using in silico -pharmacology approach along with in vitro and in vivo experiments. The aqueous extract of the flower was examined for anti-urolithiasis activity using nucleation and aggregation assays in vitro and in vivo in an ethylene glycol (EG)-induced urolithiasis model in male Wistar rats. Various physical, biochemical, and antioxidant parameters were evaluated in the serum, urine, and kidney homogenates, including body weight, urine output, SOD, MDA, creatinine level, and Blood Urea Nitrogen (BUN), followed by histopathological analysis of the kidneys to observe the effects of treatment. In vitro assays showed an increased percentage inhibition of calcium oxalate aggregation. The in vivo results were encouraging in terms of reducing metabolic stress and increasing renal function via pathways involved in inflammation, apoptosis, nitrogen metabolism, and pH balancing.

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Using medicinal plants as crude extracts for therapeutic purposes and understanding their pharmacological effects presents several difficulties. Further partitioning of crude extracts into components play crucial roles in understanding the pharmacological properties of their bioactive compounds. This study explored the biological properties of Combretum racemosum leaf, identified its bioactive compounds and molecular docking. Methanol extract of C. racemosum (MECR) leaf was prepared and successively partitioned into n-hexane (n-HFCR), ethyl acetate (EACR), n-butanol (n-BFCR) and aqueous (AFCR) fraction. Antioxidant, antidiabetic, and anti-inflammatory properties were performed using standard procedures. Bioactive compounds were identified using GC-MS and HPLC following molecular docking. Results revealed that MECR contained significant amounts of total phenol compared to the fractions while total flavonoid was abundant in n-HFCR, EACR, n-BFCR, and AFCR. Radicals (DPPH, ABTS and LPO) scavenging ability was above 50% across the samples while only the fractions demonstrated significant (p < 0.05) inhibition of amylase, glucosidase and sucrase. From this study, AFCR possessed better anti-inflammatory properties compared to other samples. Chromatography analyses revealed that both extract and fractions possessed varying concentrations of bioactive compounds such as lipoidal compounds and polyphenolic compounds. Docking analyses of the most abundant phytocompound (kaempferol) revealed strong binding interactions with human amylase, SGLT-1, SGLT-2, IL-6R, and trypsin. These findings have demonstrated the pharmacological potentials (antioxidant, antidiabetic, anti-inflammatory) of the methanol extract and fractions of C. racemosum leaf. A potential bioactive compound from the fractions of C. racemosum have been identified to possess strong molecular interactions with selected protein targets.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00507-1.

Zika virus (ZIKV), a mosquito-borne flavivirus, has emerged as a global health concern due to its association with congenital microcephaly and neurological disorders. The non-structural protein NS4A plays a pivotal role in viral replication and immune evasion by antagonizing the mitochondrial antiviral signaling protein (MAVS). In this study, we evaluated four NS4A mutations (L48M, K42E, F4L, and E8D). Only F4L and E8D showed destabilizing effects and were selected for further analysis. We used molecular docking, 300 ns molecular dynamics simulations, and binding free energy calculations to assess their effects on NS4A-MAVS binding. Stability investigations root means square deviation (RMSD) root mean square fluctuation (RMSF) and radius of gyration (Rg) revealed that both mutations changed the conformational dynamics of NS4A-MAVS complexes, with F4L displaying transitory fluctuations and E8D exhibiting long-term structural flexibility. Hydrogen bond research revealed that both mutants had stronger interaction networks with MAVS compared to the natural type. MM/PBSA computations showed that F4L and E8D had reduce binding affinities, with ΔG values of - 54.05 kcal/mol and - 56.25 kcal/mol, respectively, compared to - 61.73 kcal/mol in the wild type. The stronger electrostatic contributions observed in the E8D complex highlight its potential to further disrupt MAVS-mediated interferon induction. Collectively, these results suggest that the F4L and particularly E8D mutations enhance the immune-evasive capacity of ZIKV by stabilizing NS4A-MAVS interactions, offering insights into viral pathogenesis and providing a computational basis for therapeutic targeting of NS4A.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00540-0.

The bamboo plant Chamaedorea seifrizii is mostly used for its aesthetic qualities and air-purifying capabilities. The purpose of this study was to chemically profile and assesses the in-vitro anti-cancer properties of acetone extracts of Chamaedorea seifrizii's auxiliary inflorescence and fruits. Molecular dynamics modelling in conjunction with in silico research was also used to determine how certain components interacted with anticancer responses. The bioactive substances in fruit extracts and accessory inflorescence were identified with a gas chromatography-flame ionization detector (GC-FID). HeLa cancer cell line was used in anticancer investigations employing the MTT assay. GC-FID revealed phenethyl cinnamate (45%) and nezukol (10%) as major compounds in the auxiliary inflorescence and fruits extracts, respectively. Docking analysis revealed affirmative affinity of selected compounds with RelB receptors. With RelB receptor, docking score of phenethyl cinnamate and nezukol was - 8.3 and - 7.1 kJ/mol, respectively. The findings of the interaction studies indicated that the receptor-ligand complexes contain hydrogen bonding, alkyl bonding, and sigma interactions. The stability of best docked complexes (RelB-ligands) was further confirmed by post-MD analysis, as seen by the RMSD values. MM-PBSA analysis revealed best docked structures with binding free energy of 168 kJ mol^-1. Both bioactive compounds possess good pharmacokinetic properties as evidenced by ADMET/PASS study. Cytotoxicity studies further validated the in silico findings as the viability of HeLa cell lines reduced to 68% and 14% with Chamaedorea seifrizii's auxiliary inflorescence and fruits extracts, respectively. Chamaedorea seifrizii may be utilized to create new herbal cures for a variety of ailments, which might lead to the creation of innovative medications that have pharmacological and anticancer activities.

ABCG2, an ATP-binding cassette (ABC) transporter G2, also known as Breast Cancer Resistance Protein (BCRP), primarily found on the membrane of breast cancer cells, actively effluxes xenobiotics from cells, effectively lowering the concentration of drugs inside cells and contributing to the development of drug resistance. The present study aimed to identify potent ABCG2 inhibitors from the COCONUT database that may enhance the efficacy of anticancer drugs using computational techniques. Virtual screening of the complete COCONUT database resulted in 145 compounds with binding affinities lower than - 12.00 kcal/mol, indicating a stronger affinity than that of the reference inhibitor (febuxostat). Prime MMGBSA calculations further refined the selection, identifying the top 30 compounds with binding free energies ranging from - 65.02 to - 80.22 kcal/mol. These compounds not only conform to Lipinski's rule of five and other drug-like properties, but subsequent scaffold analysis has also identified that 12 of them possess a flavone backbone substructure. This substructure is recognized for its anticancer properties and its role as an inhibitor of ABC transporters. Binding pose metadynamics (BPMD) simulations over the top 30 ligands were used to further assess their stability. Molecules CNP0145817 (L1), CNP0114639 (L2) and CNP0288837 (L3) have demonstrated superior stability compared to the reference molecule Febuxostat (K1). Additionally, 100 ns molecular dynamics simulations were performed to explore the interaction dynamics, highlighting the key hydrophobic contacts and hydrogen bonds critical for binding stability. Important hydrophobic interactions, such as pi-pi, occur with residues such as PHE 432, PHE 439 as well as hydrogen bonds with residue ASN 436 of both chains A and B chain. The identified natural compounds exhibited strong binding affinities, stability, and favorable drug-like properties, rendering them promising candidates for overcoming ABCG2-mediated drug resistance and potentially aiding breast cancer treatment. These findings offer new avenues for drug development and improving therapeutic efficacy, although further in vitro analysis is required prior to clinical testing of the drug.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00521-3.

The current treatment scenario for antifungal drugs is limited and requires more research. Three structural classes of drugs, namely polyenes, azoles, and echinocandins, are widely used in the treatment of human fungal infections caused by Candida species. Although there is an increase in the number of antifungals, the number of issues (resistance, toxicity, and adverse effects) with these drugs has also increased. To address such issues, we have previously reported that a natural compound, Sodium lignosulfonate (LIG), that exhibits in vitro susceptibility against major Candida species, making it a potent lead. However, the pharmacological acceptance of LIG as a lead molecule is dependent on a plethora of pharmacological properties. Therefore, we have deciphered some important pharmacological properties of LIG, like aqueous solubility, lipophilicity index, pKa, bioavailability, plasma protein binding behavior, etc., in this study. Further, we have noticed a significant reduction in the growth and development of the human fungal pathogen Candida albicans cells after 24 h of treatment with LIG. Overall results strongly indicated LIG as a bioactive molecule, and the pharmacological significance of LIG could be selected for further in vivo and clinical studies to make it an effective antifungal biotherapeutic molecule in the future.

Neglected tropical diseases (NTDs) are prevalent in developing countries, leading to significant morbidity and mortality. Despite affecting millions, these diseases receive limited attention from pharmaceutical companies due to their low profitability, resulting in minimal research on novel therapies. Schistosomiasis, caused by Schistosoma mansoni, is a particularly concerning NTD that infects over 250 million people worldwide. While the current treatment with praziquantel is cost-effective, emerging drug resistance underscores the urgency for new therapeutic agents. Natural products, particularly medicinal plants like Copaifera oblongifolia, offer a promising source for novel drug discovery. Therefore, this study investigates the chemical composition of hexane fraction C. oblongifolia leaves. and its in vitro and in silico schistosomicidal activity. Through a series of extractions and gas chromatography-mass spectrometry (GC-MS) analysis, the n-hexane fraction contained triterpenes and steroids, which exhibited schistosomicidal activity against adult S. mansoni worms. The n-hexane fraction, particularly rich in these bioactive compounds, demonstrated 100% mortality at 100 µg/mL. In silico molecular docking was performed against S. mansoni thioredoxin glutathione reductase (TGR; PDB ID: 2XBI), a validated redox-regulating enzyme target. Among the identified compounds, β-amyrin showed the strongest binding affinity (- 7.4 kcal/mol, Ki: 3.7 μM), followed by lupeol (- 7.2 kcal/mol, Ki: 5.25 μM), both outperforming the reference drug praziquantel (- 6.5 kcal/mol, Ki: 7.34 μM). These findings indicate that C. oblongifolia contains compounds with promising antischistosomal activity. Further isolation, characterization, and in vivo studies are needed to confirm their potential as natural drug leads.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00501-7.