In silico pharmacology最新文献

Amyotrophic Lateral Sclerosis (ALS), commonly known as Lou Gehrig's disease, is a neurodegenerative condition characterized by the gradual deterioration of motor neurons in the brain and spinal cord, leading to muscle weakness, difficulty swallowing, speaking, and breathing. The normal ageing process has structural and functional effects on motor neurons, which may contribute to motor neuron pathology in ALS, either directly or indirectly. Although there are a few treatments available for ALS, their efficacy is limited. The objective of this study is to identify and screen potential C9ORF72 Agonists using High Throughput Virtual screening and Molecular Dynamics simulations. Using Edaravone and Riluzole as benchmark molecules, the study evaluated various chemical compounds from different databases against the target. Lead compounds from three databases (Specs_1289, Zinc_67912153 and Enamine_785152) showed binding affinity, stability and pharmacokinetic greater activity which is achieved through ML based tool; concluding that they could be used as a potential agonist for ALS-associated C9ORF72. The complexes have the highest docking scores of - 8.21, - 11.06, and - 6.934 kcal/mol with the lowest binding energy which aids the structural stability of the complex. HOMO and LUMO occupancy of the lead compounds deciphers the energy levels of the compounds with the lowest energy gap which was favorable for the chemical reactivity and chemical inertness of the molecule. Furthermore, ADME and Toxicity analysis of the compounds were evaluated through Machine Learning based tool, pkCSM. MD simulation concluded that the lead complexes showed lesser deviation and fluctuations with the higher number of hydrogen bond interactions which favors the structural stability and biological activity of the complex. This study concluded that the resultant leads from three different chemical libraries were considered as the potential therapeutic option for targeting ALS.

The study presents a comprehensive approach to target prediction for gout (DOID: 13189) through the integration of disease ontology and network-based strategies. A total of 13 proteins associated with gout were identified and analyzed using the STRING database, which visualized protein-protein interactions (PPIs). Cytoscape, enhanced with the CytoHubba plugin, was used to prioritize key proteins, identifying Solute loading carrier family 22 member 12 (SLC22A12) and SLC22A9 genes as the most promising targets based on their high degree of interaction. Sequence alignment of these proteins (Urate Anion Exchanger 1-URAT1 and Organic anion transporter 7-OAT7) revealed significant homology, suggesting that they play complementary roles in uric acid transport and gout pathogenesis. Molecular docking by AutoDock Vina and AutoDock4 of whole Indian Medicinal Plants, Phytochemistry And Therapeutics (IMPPAT) database, Food and Drug Administration (FDA) Approved Drugs revealed three leads from the Woodfordia fruticosa (Heterophylliin A), Arctium lappa (Arctignan D), and Oroxylum indicum (Scutellarein 7-rutinoside) demonstrated strong binding affinities with URAT1 through favorable docking interactions over the best docked Fostemsavir and URAT1 inhibitors (Lesinurad and Benzbromarone) indicating their potential as modulators of uric acid transport. The molecular dynamics simulations (MDS) of URAT1 in membrane environment with the identified compounds by Desmond further supported that all three leads exhibited superior binding stability, binding energy and interaction profiles compared to the existing drugs. The results highlight the potential of these phytochemicals upon further experimental validation as therapeutic agents for gout. This integrative bioinformatics and computational approach provide a robust framework for discovering potent drug target and bioactive compounds with strong potential for effective gout treatment if further validated through in vitro and in vivo assays.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00476-5.

Type 2 diabetes is a prevalent disease that continues to pose a significant health burden worldwide. Despite the availability of various drugs for its management, the number of diagnoses and mortalities is persistently on the rise. Alpha-glucosidase inhibition has emerged as a promising therapeutic strategy to prevent postprandial hyperglycaemia. One approach in drug discovery is drug repurposing, which involves investigating existing drugs for new therapeutic indications. This study used a three-stage molecular docking approaches to screen the DrugBank database for potential alpha-glucosidase inhibitors against N-terminal maltase glucoamylase (ntMGAM) target. We selected 10 compounds with top docking performance, and rescoring these compounds with MMGBSA calculations produced arbekacin, neamine, and sisomicin with a binding free energy of - 72.13, - 55.14, and - 69.07 kcal/mol, respectively, as the top three compounds. These compounds were subsequently analysed and compared with the standard drug, acarbose for their protein-binding stability using molecular dynamics simulation (MDS) approach. The MDS analysis suggests that sisomicin exhibited the most stable interactions and stronger post-MDS binding free energy with alpha-glucosidase. These findings suggest that sisomicin is a potential inhibitor of alpha-glucosidase, and a novel candidate for drug repurposing in antidiabetic therapy.

Flavonoids are bioactive polyphenols with enzyme inhibitory properties, making them promising candidates for modulating postprandial glucose metabolism. This study evaluated twelve structurally diverse flavonoid derivatives for their inhibitory potential against pancreatic alpha-amylase and alpha-glucosidase using an integrated in silico and in vitro approach. Molecular docking revealed binding affinities ranging from - 9 to - 5 kcal/mol, with flavan-4-ols, taxifolin, and epigallocatechin showing the strongest interactions at catalytic residues ASP197 and GLU233 (amylase) and ASP327 and ASP443 (glucosidase). Molecular dynamics simulations and free energy calculations confirmed complex stability, though correlations with in vitro data were modest. Kinetic assays demonstrated predominantly noncompetitive-uncompetitive and uncompetitive inhibition, reducing V_max without altering K_m. Acarbose showed a K_i' of 25 ± 0.4 µM for amylase and a K_i of 73 ± 0.5 µM for glucosidase, while several flavonoids, including 7-hydroxyflavanone, 2'-hydroxyflavanone, 4'-hydroxyflavanone, liquiritigenin, naringenin, eriodictyol, and ampelopsin displayed lower K_i' values between 9 and 21 µM for amylase and between 6 and 19 µM for glucosidase, indicating stronger affinity for the enzyme-substrate complex. These results confirm that hydroxylated flavonoids preferentially target the enzyme-substrate complex through allosteric mechanisms, often surpassing acarbose in binding efficiency. The combined in silico and in vitro workflow provides a validated strategy for systematically evaluating flavonoid derivatives as potential enzyme-targeted therapeutics for diabetes management.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00493-4.

Alpha-glucosidase plays a critical role in carbohydrate digestion and is a key therapeutic target for controlling postprandial hyperglycemia in type 2 diabetes mellitus (T2DM). In this study, a comprehensive computational approach was employed to screen and evaluate flavonoids from Mentha arvensis as potential alpha-glucosidase inhibitors. A total of 183 flavonoid compounds were retrieved from the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT) database and screened using virtual screening and molecular docking techniques. Four lead compounds, IMPHY004660, IMPHY004038, IMPHY004611, and IMPHY005431, were identified based on their high binding affinities and favourable interaction profiles. These complexes underwent molecular dynamics simulations for 200 nanoseconds to assess conformational stability, binding interactions, and dynamic behaviour. Binding free energy calculations using the MM/GBSA method showed that IMPHY004038 had the strongest affinity with a binding energy of - 31.13 ± 6.50 kcal/mol, closely matching the reference control molecule (alpha maltotriose) with a binding energy of - 30.30 ± 19.98 kcal/mol. Free energy landscape analysis further demonstrated that the protein ligand complexes remained stable, with well-defined energy minima and minimal conformational changes. Hydrogen bond analysis confirmed sustained interactions over the simulation period, particularly for IMPHY004038. These computational findings indicate that flavonoids from Mentha arvensis are promising candidates for alpha-glucosidase inhibition. Future experimental validation through in vitro and in vivo studies is recommended to confirm their potential therapeutic role in managing type 2 diabetes mellitus.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00485-4.

Limited research has been conducted on the mechanistic action of Artemisia annua against hepatocellular carcinoma (HCC) and associated comorbidities, underscoring its potential as a flagship traditional plant for future pathological investigations. This study employed an integrative network pharmacology approach to elucidate the interplay between key metabolites, therapeutic targets, and HCC-modulated pathways. Our findings identified artemisinin as the predominant bioactive compound, exerting regulatory effects through critical targets such as AKT1, EGFR, HSP90AA1, and ESR1. Molecular docking revealed robust binding interactions between artemetin and these targets, with docking scores ranging from -9.5 to -17.4 kcal/mol, supported by low RMSD values (< 2.0 Å), indicative of stable complexes. UHPLC‒MS analysis of the methanol-based extract revealed multiple anticancer and antidiabetic compounds, predominantly flavonoids. In vitro validation demonstrated significant dose-dependent inhibition of HepG2 cell viability (up to 96.25% ± 0.5 reduction at 200 μM) and notable α-amylase inhibitory activity (30.22% at 1 µg/mL), albeit less potent than that of acarbose. Collectively, our in silico and experimental results provide a mechanistic foundation for the anti-HCC and antidiabetic potential of Artemisia annua, highlighting its multitarget therapeutic properties. These findings warrant further validation through in vitro and in vivo studies to advance its clinical application.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00462-x.

Mycoplasma genitalium (M. genitalium) has evolved into a superbug due to the emergence of antimicrobial resistance and is a growing concern with only a few treatment options. The emergence of antibiotic resistance has made it essential to create novel types of antibiotics or medications to treat this particular pathogen. The thymidylate kinase (tmk) enzyme may be a good drug target for M. genitalium survival as it is pivotal in DNA synthesis. Structure-based drug design approaches targeting tmk of M. genitalium have been established to find potent inhibitors efficiently. Phellodenol G, Phyllanthosterol, and stigmasterol were identified as the three most potent phytochemical inhibitors in this study, with binding energies of - 9.64, - 9.64, and - 9.54 kcal/mol, respectively. The active site residues Arg-53, Ser-101, and Leu-56 appear to be critical in the binding of potent inhibitors. As per molecular dynamics analysis, all three phytochemical inhibitors have stable interactions with tmk. MM-PBSA analysis indicates that phytochemical inhibitors are stable. Taken together, our computational findings may aid in the development of potential drugs to treat and mitigate the severity of M. genitalium infection (MGI).

Maslinic acid (MA), a plant-derived pentacyclic triterpene, was compared to the FDA-approved drugs dasatinib (DAS) and doxorubicin (DOX) to determine its antileukemic potential. Chronic Myeloid Leukaemia and Acute Myeloid Leukaemia were caused by mutations in the BCR-ABL kinase which is regulated by CBL-kinase and FLT3 over the decade. This present investigation aimed to identify the antileukemic potential of MA as compared to the FDA-approved drugs dasatinib (DAS) and doxorubicin (DOX) via an in silico approach. MA had strong binding affinity with leukemic target proteins, with similar affinity and stability to DAS and DOX. Pharmacokinetic and toxicology studies revealed that MA has drug-like characteristics and a lower toxicity profile (LD50: 205 mg/kg). MD simulations during a 100 ns period revealed that MA obtained stable binding conformations, with RMSD, RMSF, Rg, and hydrogen bonding evaluations indicating performance comparable to the reference medicines. Thus, these results illustrate that MA may act as a natural scaffold with antileukemic properties and call for additional experimental confirmation.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00478-3.

Breast cancer remains a major global health concern, underscoring the need for new, multitarget therapeutic strategies. This study employed an integrative computational approach combining molecular docking, MM/GBSA binding free energy analysis, ADMET profiling, and Density Functional Theory (DFT) to evaluate 100 flavonoids against four key breast cancer targets which are; ERα, PI3K, HER2, and EGFR. Comparative docking with five reference drugs (Alpelisib, Buparlisib, Lapatinib, Gefitinib, and Afatinib) identified nine flavonoids; Sphaerobioside, Avicularin, Nicotiflorin, Myricetin, Quercitrin, Rutin, Isoquercetin, Didymin, and Robinin as promising candidates with favorable binding affinities and stable receptor interactions. MM/GBSA results supported the docking outcomes, revealing strong binding stability across multiple targets. ADMET predictions suggested acceptable pharmacokinetic and safety profiles for several compounds, while DFT analysis provided insight into their electronic stability and reactivity. Collectively, these findings highlight the multitarget inhibitory potential of selected flavonoids and demonstrate how integrated computational profiling can accelerate the discovery and optimization of natural product-based anticancer agents.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00489-0.

PfMDR1, a key transporter protein in Plasmodium falciparum, contributes to antimalarial drug resistance by actively expelling drugs like chloroquine from the parasite's digestive vacuole, lowering their intracellular efficacy. In this study, our aim was to identify the antimalarial compounds with unknown targets on the basis of cellular assays from the Chembl and IUPHAR databases against the target protein PfMDR1, having PDB ID: 8JWI, using molecular docking with GLIDE and GOLD. The top-ranking compound demonstrated a GLIDE docking score of - 12.169 kcal/mol, surpassing the benchmark compound (- 5.435 kcal/mol) and other experimentally tested drugs. Post-docking analyses using LigPlot and PyMOL revealed strong hydrogen bonding and hydrophobic interactions with key active site residues. Binding affinity predictions using X-SCORE further supported the superior binding of the top compound. To evaluate stability and inhibitory potential, we performed molecular dynamics (MD) simulations using GROMACS, analyzing protein-ligand interactions throughout the trajectory. The top compound maintained stable binding throughout the simulation, with minimal fluctuations. The binding free energy calculations using MM/PBSA method further confirmed its inhibitory effect, with a binding free energy of - 130.971 ± 14.283 kJ/mol, significantly higher as compared to the benchmark and other experimentally tested compounds, indicating stronger and more stable interactions. These findings suggest that the identified inhibitor exhibits greater potency against PfMDR1 than the benchmark and other screened antimalarial drugs, making it a promising candidate for overcoming P. falciparum drug resistance. This study provides valuable insights for future structure-based drug design targeting PfMDR1 and developing next-generation antimalarial therapies.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00486-3.