The papain-like protease (PLpro) of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) plays a key role in viral polyprotein processing and suppression of host innate response, making it a valuable target for the development of anti-viral drugs. However, the availability of potent small-molecule inhibitors of PL pro remains limited. The current study was designed to synthesize novel indole-tagged thia/oxadiazole scaffolds (10–23) and their inhibition profile against PL pro was tested, with GRL0617 used as a reference inhibitor. The evaluation revealed a broad spectrum of inhibitory potency, with IC 50 values ranging from 0.7934 μM to 23.79 μM. Remarkably, compounds 13 (IC 50 = 0.7934 μM), 11 (IC 50 = 1.118 μM), and 18 (IC 50 = 1.446 μM) demonstrated superior inhibitory potency relative to the reference inhibitor GRL0617 (IC.. = 2.40 μM). Based on structure-activity relationship (SAR) investigations, the alterations to the aryl ring substituents attached to the thia/oxadiazole scaffold were identified to be the key factor for modulating inhibitory potency. The molecular docking study of the most active compound 13 demonstrated a favorable binding conformation within the PL pro , highlighted by stable hydrogen bonding and hydrophobic interactions with key catalytic residues, thereby enhancing inhibitory potency. Additionally, DFT calculations and ADMET analyses of potent compound 13 showed favorable electronic properties and suitable pharmacokinetic properties, supporting its potential for further optimization. Altogether, these findings identify compound 13 as a potent early-stage enzymatic hit that provides a valuable starting point for further structural optimization toward the development of improved SARS-CoV-2 PL pro inhibitors.

Plants and their phytomolecules have been employed for centuries to treat various illnesses, including cognitive impairments. In modern drug discovery, phytomolecule libraries serve as an important source for identifying novel therapeutic agents, particularly for complex diseases, as de novo chemical synthesis is often time-consuming and expensive. In this study, a total of 44,085 Central Nervous System (CNS)-targeting phytomolecules were retrieved from the ChemDiv library and systematically screened for their potential as inhibitors of the phosphodiesterase-1 (PDE1) receptor using molecular modeling tools. PDE1 is a key enzyme predominantly expressed in brain tissues that hydrolyzes the 3’,5’-cAMP (3’,5’-cyclic Adenosine Monophosphate) and 3’,5’-cGMP (3’,5’-cyclic Guanosine Monophosphate) and into their inactive monophosphate counterparts, 5’-cAMP and 5’-cGMP. Cyclic nucleotides are essential for regulating neuronal signaling pathways. An initial molecular docking analysis identified 10 phytomolecules exhibiting strong binding affinities ranging from −11.97 to −12.54 kcal×mol −1 , and significant interactions with key amino acid residues within the active site of PDE1. Molecular dynamics simulations confirmed that four protein-ligand complexes (D361-0316-PDE1, L977-1068-PDE1, J081-0995-PDE1, and L977-1023-PDE1) remained structurally stable for up to 100 nanoseconds. Further, density functional theory (DFT) studies confirmed the electronic stability of these molecules. ADMET and drug-likeness evaluations predicted pharmacokinetics and toxicity profile. Overall, the findings suggest that these four phytomolecules may serve as promising PDE1 inhibitors for the management of cognitive impairment.

Citrus fruits and their bioactive components have demonstrated significant therapeutic potential in the management of various diseases. The present study aims to identify potent citrus flavonoids that could act as dual PI3K/mTOR inhibitors against ovarian cancer. Using a network pharmacology framework, the potential targets of citrus flavonoids were mapped against genes associated with ovarian cancer, revealing key pathway enrichment within the PI3K/mTOR signaling cascade. A natural compound library derived from the Eximed database was employed for the study, and High-Throughput Virtual Screening (HTVS) was performed to identify compounds showing favorable interactions with PI3K (PDB ID: 5DXT) and mTOR (PDB ID: 5GPB). Based on Standard Precision (SP) and extra precision (XP) docking results, hesperidin was identified as a promising candidate for further investigation. Additionally, two other flavonoids, hesperetin and naringin, were selected based on literature evidence. Further computational analyses, including MM-GBSA binding free energy calculations, ADME prediction, molecular dynamics simulations and water map analysis, indicated that hesperidin exhibits strong binding stability and favorable interaction profiles. These findings suggest that hesperidin may serve as a promising lead compound for further in-vitro and in-vivo studies aimed at developing effective dual PI3K/mTOR inhibitors against ovarian cancer therapy.

Aberrant expression of bruton’s tyrosine kinase (BTK) plays a major role in progression of B-cell malignancies and autoimmune disorders, highlighting the need for effective and selective BTK inhibitors. A series of 45 pyrrolopyrimidine derivatives were selected for in-silico study from the literature. A 3D-QSAR and pharmacophore model was utilized to design novel compounds; they were subsequently generated through R group enumeration based on the QSAR data and further evaluated through molecular docking and virtual screening. The model AADHR_1 was chosen as the best pharmacophore model. The 3D-QSAR analysis yielded statistically robust models. The atom based model exhibited excellent correlation coefficient (R 2 = 0.8831), and cross validation coefficient (Q 2 = 0.8675), while the field based demonstrated correlation coefficient of R 2 =0.8498 and Q 2 =0.855. A total for 1752 compounds were generated through R group enumeration for production of new compounds. Among them R1 demonstrated the best binding affinity (- 7.87 kcal/mol, PDB ID: 5P9J) with key binding interactions at TYR551, GLN412, and LYS430. Molecular dynamics (MD) simulations further confirmed the stability of these interactions under dynamics conditions. Furthermore, ADME and physiochemical properties confirmed drug likeness, bioavailability, and a favourable pharmacokinetic profile of the designed compounds. Among the designed compounds, R1 exhibited the highest binding affinity, superior interaction stability in MD simulations, and balanced ADME characteristics, making it most potent. Overall, this study provides considerable insights into the rational computational design of pyrrolopyrimidine based BTK inhibitors for advancing these candidates into experimental validation and clinical advancement.

In the current study, the cytotoxic potential of the methanol extract of Astragalus tephrosoides was examined by a comprehensive approach based on its phytochemical profiling analysis with in vitro cytotoxic assays and computational modelling. The extract showed significant cytotoxicity against MCF-7 breast cancer cells with value of IC 50 = 2.915 ± 0.163 μg/mL indicating it’s prospective as anti-proliferative agent. Two-thirds of these compounds were identified in extract by GC-MS analysis, which revealed 23 representative phytochemicals that may also be cancer pathway modulating, such as purines, fatty acids and phytol. Molecular docking analysis demonstrated that CP-23, CP-20, and CP-9 exhibited strong binding affinities toward the key therapeutic targets CDK4 and EGFR. Structural Interaction Fingerprint (SIFt) analysis further identified crucial binding residues, providing insight into their potential multi-target engagement. In silico ADMET profiling and DFT calculations suggested favorable pharmacokinetic characteristics and satisfactory electronic stability for the top-performing compounds. Additionally, molecular dynamics simulations confirmed the stability of the ligand protein complexes under near-physiological conditions. Collectively, these findings suggest that A. tephrosoides contains promising bioactive constituents capable of acting as multi-target modulators against breast cancer, warranting further experimental validation.

In the present study, we assessed the neuroprotective efficacy of the bicyclic monoterpene fenchone in a rotenone-induced rat model of Parkinson’s disease through integrated in silico and in vivo investigations. Molecular modeling indicated that fenchone is very lipophilic (LogP = 2.40) and contains a mostly hydrophobic pharmacophore. It showed good binding affinity with the dopamine D 2 receptor (-5.84 kcal/mol) and similar results to those obtained from levodopa (-5.7 kcal/mol). The results of density functional theory revealed that fenchone has high chemical hardness (3.175 eV) and a large HOMO-LUMO energy gap (6.35 eV), indicating molecular stability. The stability of the fenchone-dopamine D 2 receptor complex in molecular dynamics for 100 ns was confirmed by stable root mean square deviation values and radius of gyration. In vivo, fenchone (200 mg/kg) treatment significantly improved motor performance by decreasing pole test latency and restoring stair test, wood walk test, wire hang and rotarod performance. Biochemical analyses demonstrated that fenchone normalized dopamine levels; increased the activities of antioxidant markers such as catalase and superoxide dismutase; and reduced glutathione levels while decreasing malondialdehyde levels. Histopathologically, nigral neurons were preserved in the presence of levodopa. Taken together, our results suggest that fenchone has the potential to be a novel multimodal disease-modifying agent for PD by acting on the dopamine D2 receptor and exerting antioxidant and neuroprotective effects.

Staphylococcus aureus remains a critical ESKAPE pathogen due to its multidrug resistance and reliance on virulence-associated enzymes. In this study, an integrative in silico pipeline combining molecular docking, redocking-based validation, molecular dynamics (MD) simulations, and pharmacokinetic profiling was applied to prioritize Psidium guajava metabolites targeting two functionally distinct proteins: the essential peptidoglycan biosynthesis enzyme MurE and the antivirulence factor sortase A (SrtA). Twenty-one metabolites were docked against both targets, and reference redocking experiments were performed using the co-crystallized ligand for MurE and quercetin for SrtA to validate the docking protocol. Flavonoids quercetin and myricetin exhibited the strongest binding affinities toward MurE (≈-9.8 to -9.9 kcal·mol -1 ) and displayed stable MD behavior over 100 ns, characterized by low backbone RMSD values (0.25-0.40 nm), limited RMSF fluctuations confined to terminal regions, a stable radius of gyration, and consistent potential energy profiles, indicating persistent interactions within the MurE catalytic site. In contrast, SrtA complexes with rutin and oleanolic acid showed pronounced conformational rearrangements during MD simulations, with large backbone RMSD excursions (≈2-9 nm) and fluctuating compactness, with partial stabilization emerging toward the end of the 100 ns trajectory (approximately after ~60-80 ns), consistent with dynamic or transient binding rather than stable inhibition. Pharmacokinetic analyses highlighted quercetin and myricetin as the most drug-like candidates among the evaluated metabolites. Overall, the results support a complementary, target-selective strategy, identifying MurE as a robust enzymatic target for P. guajava flavonoids, while SrtA interactions are better interpreted as potential antivirulence modulation rather than strong dual-target inhibition. This refined framework provides a realistic and mechanistically grounded basis for prioritizing plant-derived scaffolds against S. aureus.

In this research, in vitro and in silico drug discovery approaches were used to evaluate the antibacterial potential of a few unexplored freshwater green algae, namely Oedogonium angustistomum, Ulothrix variabilis and Mougeotia pulchella, as well as their fatty acids and peptides. In an in vitroantimicrobial assessment, the methanol and methanol crude extracts of U. variabilis significantly inhibited the growth of S. aureus and E. coli, showing inhibition zones of 14 mm and 13 mm, respectively. However, in the antifungal experiment, all extracts, except petroleum benzine, showed excellent inhibitory effects on C. albicans and F. oxysporum, with zones of inhibition ranging from 7.33 mm to 18 mm and 40.00% to 51.33%, respectively. In the minimum inhibitory concentration analysis, the methanol extract of U. variabilis effectively reduced the viability of S. aureus at a dose of 30 [Formula: see text]g/mL. Molecular docking analysis showed that 2-(S-glutathionyl) acetyl glutathione, Endomorphin-2 and APGPR enterostatin had stronger binding affinities with all microbial proteins than fatty acids, with docking scores of –8.315 kcal/mol, –8.687 kcal/mol, –8.313 kcal/mol and –7.054 kcal/mol, respectively. In the MD simulations, all hit peptide-protein complexes showed excellent binding stability, with a stable RMSD range of ¡2.8 Å and binding strengths of up to 99% for the simulation of 200 ns. These findings suggest that the peptides identified in algae have the potential to control antimicrobial-resistant strains and opportunistic fungal pathogens. However, further research is needed to ensure the safety and efficacy of these peptide compounds in lab-to-clinical applications.