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Punicalagin is the most bioactive pomegranate polyphenol with high antioxidant and free-radical scavenging activity and can potentially cure different ailments related to the cardiovascular system. The current research work was envisioned to predict the targeting efficiency of punicalagin (PG) nanoparticles to the macrophages, more specifically to bone marrow macrophages. For this, we selected mannose-decorated PLGA-punicalagin nanoparticles (Mn-PLGA-PG), and before formulating this nanocarrier in laboratory settings, we predicted the targeting efficiency of this nanocarrier by in silico analysis. The analysis proceeded with macrophage mannose receptors to be acquainted with the binding affinity and punicalagin-based nanocarrier interactions with this receptor. In silico docking studies of macrophage mannose receptors and punicalagin showed binding interactions on its surface. PG interacted with hydrogen bonds to the charged residue ASP668 and GLY666 and polar residue GLN760 of the Mn receptor. Mannose with a docking score of −5.811 Kcal/mol interacted with four hydrogen bonds and the mannose receptor of macrophage, and in PLGA, it showed a −4.334 Kcal/mol docking score. Further, the analysis proceeded with density functional theory analysis (DFT) and HOMO–LUMO analysis, followed by an extensive 100 ns molecular dynamics simulation to analyse the trajectories showing the slightest deviation and fluctuation. While analysing the ligand and protein interaction, a wonderful interaction was found among the atoms of the ligand and protein residues. This computational study confirms that this nanocarrier could be a promising lead molecule to regulate the incidence of drug-induced neutropenia. Furthermore, experimental validation is required before this can be stated with complete confidence or before human use.

Breast cancer is one of the most prevalent cancers worldwide, ranked as the second most diagnosed cancer and the fourth leading cause of cancer-related deaths. Despite the availability of FDA-approved therapies, limitations such as drug resistance and off-target effects highlight the need for novel, multitargeted therapeutic agents. In this study, we aimed to identify and design an in-silico promising multitarget drug for breast cancer by simultaneously targeting three critical proteins: Glucocorticoid Receptor, Estrogen Receptor-alpha (ER-alpha), and Cyclin-Dependent Kinase 2 (CDK2). FDA-approved drugs corresponding to these targets were initially subjected to multitarget molecular docking to evaluate their binding affinities. Based on this screening, the 15 highest-ranking ligands were selected and underwent molecular enumeration, resulting in the generation of 14,750 novel derivative compounds. The re-docking identified 1-((R)-2,3-dihydroxypropyl) −3-(3-((R)-1–5-methyl-1H-pyrrolo [2,3-b]pyridin-3-yl)ethyl)phenyl) urea (DdpMPyPEPhU) (Patent No. 202024101028.0) as a promising multitarget candidate. The compound exhibited enhanced binding pocket engagement through numerous stabilising interactions, including hydrogen bonds, π-π stacking, and π-cation interactions, with high docking scores (–14.869 to –4.57 kcal/mol) and favourable Molecular Mechanics Generalised Born Surface Area (MM-GBSA) energies (–72.32 to –11.97 kcal/mol). Comparative docking and pharmacokinetic analyses with standard drugs Lapatinib and Tamoxifen indicated better drug-like properties and pharmacokinetic advantages for DdpMPyPEPhU. Additional validation using Density Functional Theory (DFT) optimisation, 5 ns WaterMap analysis, and 250 ns molecular dynamics simulations under neutralised conditions confirmed structural stability and strong intermolecular interactions, supported by binding free energy calculations. Overall, our computational findings suggest that DdpMPyPEPhU is a promising therapeutic candidate for breast cancer, providing a rational basis for further experimental evaluation.

Ovarian cancer, a formidable gynaecological malignancy, poses a significant global health challenge, and it is characterised by late-stage diagnosis and a high mortality rate. Even in its early stages, when treatment choices are scarce, ovarian cancer is still a complicated cancer to treat. In this work, we used computational approaches to find putative Traditional Chinese Medicine (TCM) inhibitors that target Phosphoserine Aminotransferase 1 (PSAT1), a crucial enzyme linked to the development of early-stage ovarian cancer. Using a methodical screening approach, we chose a panel of TCM compounds and prepared them, expected to interact with PSAT1. We next evaluated the binding affinities using molecular docking, which helped to identify Coniferin and Tetrahydrocurcumin compounds as potent inhibitors with the docking score of -8.8 kcal/mol and -8.9 Kcal/mol, respectively, and compared to the native ligand. The inhibitory effects of Coniferin and Tetrahydrocurcumin compounds were evaluated with the Pharmacokinetic studies and compared with the standard values, which resulted in an utter performance against each descriptor of the QikProp and performed the Molecular Interaction Fingerprints that resulted in the most interaction residues with counts were 4GLY, 4ASN, 4HIE, 4SER, 4THR, 3ARG and many more. Further, 100ns MD Simulation was performed in neutralised water, resulting in entirely stable deviations, fluctuations, and many intermolecular interactions, and the MM studies on all 1000 trajectories have supported the complex’s stability. The computational studies have shown a completely stable performance that supports Coniferin, and Tetrahydrocurcumin can be a potent inhibitor of PSAT1. However, further experimental works are needed to confirm this study.

Neutropenia, characterized by a critical reduction in neutrophils, demands targeted therapeutic strategies to enhance the delivery efficiency of granulocyte colony-stimulating factor (G-CSF) specifically to bone marrow macrophages. This study focused on engineering mannose-modified poly(D, L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) to achieve ligand-directed delivery of G-CSF. Mannose anchoring was achieved via Ethylenediamine (EDA)-mediated chemical ligation using N-hydroxysulfosuccinimide (NHS) and dicyclocarbodiimide as coupling agents, resulting in Mn-EDA-PLGA NPs. G-CSF-loaded and placebo NPs were fabricated through a multiple emulsion solvent evaporation method and subjected to comprehensive physicochemical characterization. The developed placebo Mn-EDA-PLGA NPs measured 199 ± 12 nm, while G-CSF-loaded Mn-EDA-PLGA NPs measured 153 ± 12.2 nm, both exhibiting a negative surface charge of − 40.07 ± 1.1 mV and − 34.9 ± 1.9 mV, respectively. Polydispersity index values were low (0.34 and 0.41), indicating uniform particle distribution. Entrapment efficiencies were significant, with the optimized G-CSF-loaded formulation achieving 72.6% drug encapsulation efficiency and drug loadings of 5 µg and 3 µg for placebo and active NPs, respectively. Scanning electron microscopy confirmed spherical morphology with smooth surfaces. Biological evaluation using scintigraphy and flow cytometry in J774.2 macrophage cells validated the targeting efficiency of mannose-modified NPs. Furthermore, molecular docking and molecular dynamics simulations substantiated the stability and interaction profile of G-CSF within the nanocarrier system. The convergence of in vitro, in vivo, and silico findings underscores the potential of Mn-EDA-PLGA NPs as a robust delivery vehicle for G-CSF, offering enhanced bone marrow macrophage targeting. This targeted approach holds promise for improving therapeutic outcomes in neutropenia by maximising drug localization and minimising systemic exposure.

Breast cancer is one of the most prevalent cancers worldwide, ranked as the second most diagnosed cancer and the fourth leading cause of cancer-related deaths. Despite the availability of FDA-approved therapies, limitations such as drug resistance and off-target effects highlight the need for novel, multitargeted therapeutic agents. In this study, we aimed to identify and design an in-silico promising multitarget drug for breast cancer by simultaneously targeting three critical proteins: Glucocorticoid Receptor, Estrogen Receptor-alpha (ER-alpha), and Cyclin-Dependent Kinase 2 (CDK2). FDA-approved drugs corresponding to these targets were initially subjected to multitarget molecular docking to evaluate their binding affinities. Based on this screening, the 15 highest-ranking ligands were selected and underwent molecular enumeration, resulting in the generation of 14,750 novel derivative compounds. The re-docking identified 1-((R)-2,3-dihydroxypropyl) -3-(3-((R)-1-5-methyl-1H-pyrrolo [2,3-b]pyridin-3-yl)ethyl)phenyl) urea (DdpMPyPEPhU) (Patent No. 202024101028.0) as a promising multitarget candidate. The compound exhibited enhanced binding pocket engagement through numerous stabilising interactions, including hydrogen bonds, π-π stacking, and π-cation interactions, with high docking scores (-14.869 to -4.57 kcal/mol) and favourable Molecular Mechanics Generalised Born Surface Area (MM-GBSA) energies (-72.32 to -11.97 kcal/mol). Comparative docking and pharmacokinetic analyses with standard drugs Lapatinib and Tamoxifen indicated better drug-like properties and pharmacokinetic advantages for DdpMPyPEPhU. Additional validation using Density Functional Theory (DFT) optimisation, 5 ns WaterMap analysis, and 250 ns molecular dynamics simulations under neutralised conditions confirmed structural stability and strong intermolecular interactions, supported by binding free energy calculations. Overall, our computational findings suggest that DdpMPyPEPhU is a promising therapeutic candidate for breast cancer, providing a rational basis for further experimental evaluation.