Atherosclerosis is primarily induced by endothelial dysfunction, a pivotal initial occurrence that transforms the arterial wall from a dormant barrier to a pro-inflammatory, pro-thrombotic condition. G protein-coupled receptors (GPCRs) serve as essential sensors governing homeostasis, rendering them crucial therapeutic targets. Nonetheless, conventional unbiased GPCR medications sometimes provoke dose-limiting systemic adverse effects due to pleiotropic transducer engagement and widespread on-target activity across non-vascular tissue beds. Biased GPCR signaling constitutes a revolutionary pharmaceutical paradigm that addresses these constraints. By employing strategically chosen ligands or allosteric modulators that stabilize certain receptor conformations, one can selectively activate vasoprotective, barrier-enhancing pathways while dissociating harmful inflammatory responses. This paper examines the mechanisms of functional selectivity among main endothelium GPCR families, including angiotensin II, sphingosine-1-phosphate, atypical chemokine, and β-adrenergic receptors. Additionally, we highlight the potential of high-resolution structural biology, single-cell transcriptomics, spatial omics, and dynamic bioengineered models as emerging translational instruments to guide future drug discovery. Engineering endothelium-targeted biased therapies is a precise, pathway-specific approach to halt plaque progression, stabilize susceptible lesions, and transform the future of precision cardiovascular care.

Glycan-mediated communication between immune cells and their environment is orchestrated by a structurally diverse set of lectin receptors whose exquisite ligand specificity governs both protective immunity and pathological immune evasion. Among these, the C-type lectin DC-SIGN, the proto- and chimera-type Galectins, and the immunoglobulin-like Siglecs occupy central positions in shaping innate and adaptive immune responses. Understanding the molecular basis of these interactions including the thermodynamics and kinetics of binding, the roles of multivalency and avidity, and the structural dynamics of recognition pockets is essential for both decoding immune regulation and developing precision therapeutics. This review presents a mechanistic and comparative analysis of glycan recognition across all three lectin families. We discuss how pathogens exploit these receptors to evade immunity, how tumors deploy hypersialylation and galectin secretion as non-canonical immune checkpoints, and how structural knowledge has enabled rational ligand-based drug design. Current therapeutic strategies including glycomimetic inhibitors, monoclonal antibodies, clustered regularly interspaced short palindromic repeats (CRISPR)-mediated glycoengineering, and chimeric antigen receptor T-cell (CAR-T) cell approaches are critically evaluated alongside emerging technologies in AI-assisted glycochemistry, single-cell glycomics, spatial glycoproteomics, and glycan nanoparticle delivery. We conclude by outlining a framework for precision glycoimmunotherapy in cancer, infection, fibrosis, and autoimmunity, positioning lectins as dynamic immune checkpoints whose structural plasticity makes them compelling and tractable drug targets.

KRAS is a major oncogenic target in precision oncology because of its conformational flexibility and limited druggability. This study employed an integrated multiscale computational strategy to identify and characterize novel KRAS inhibitors with improved structural, thermodynamic, and electronic stability. Virtual screening and molecular docking identified three promising compounds, F3409-0029, F6725-0291, and F3408-0006, with strong affinity for the KRAS active site. To assess conformational stability and ligand adaptability, we performed 500 ns molecular dynamics simulations for all complexes. Among them, the KRAS-F3408-0006 complex showed the highest structural stability, as reflected in stable RMSD values, reduced residue fluctuations, compact conformational behavior, and sustained ligand accommodation throughout the trajectory. MM/GBSA calculations revealed favorable binding energetics dominated by van der Waals and electrostatic interactions. Per-residue MM/GBSA decomposition also identified key energetic hotspots that contribute to F3408-0006 binding to KRAS. Principal component analysis and free energy landscape profiling further showed restricted collective motions and a dominant low-energy conformational basin, supporting greater thermodynamic stability than the reference inhibitor. Density functional theory and QM/MM analyses additionally confirmed favorable frontier molecular orbital distribution and stable quantum-level interactions within the binding cavity. Overall, F3408-0006 emerged as a promising KRAS inhibitor candidate for future experimental validation.

TGF-beta-activated kinase 1 (TAK1) is a critical regulator of inflammatory and oncogenic signaling pathways and represents a promising therapeutic target for diseases ranging from chronic inflammation to cancer. However, existing therapies targeting downstream mediators often face limitations such as drug resistance and inconsistent efficacy. Here, we report on drug repurposing to discover FDA-approved compounds that can suppress TAK1 activity. Molecular docking of 3500 drugs from the DrugBank database was performed, followed by drug profiling, biological activity analysis, and 500-nanosecond molecular dynamics (MD) simulations via a multi-step computational protocol. The systematic screening identified a few hits where two drugs, nilotinib and dabrafenib, showed appreciable binding affinity to the ATP-binding site of TAK1 and showed appropriate drug profiles. Stable interaction analyses indicated consistent engagement of catalytic residues and structural motifs essential for ATP binding and subsequent TAK1 function. MD simulations further indicated stable TAK1-ligand complexes for both nilotinib and dabrafenib, with persistent hydrogen-bonding interactions and maintenance of protein compactness throughout the simulations. These findings support the repositioning of nilotinib and dabrafenib as potential TAK1-targeting compounds toward therapeutic development against inflammation-driven pathologies and cancer. Experimentally validating these insights at the level of cells, tissues, organs, and body systems is necessary to translate computational insights into practical use for therapeutic development.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, Tau hyperphosphorylation, and cholinergic dysfunction, necessitating multi-target therapeutic strategies. This study evaluated phycobiliproteins (PBPs) as dietary precursors of neuroprotective compounds acting on multiple AD pathways. After simulated gastrointestinal digestion, peptide fractions P1 (GCAPR), P2 (QAGDQL), and P3 (AGDASVL) were assessed alongside phycocyanobilin (PCB) using molecular docking against Beta-secretase 1, Glycogen synthase kinase 3 beta, Acetylcholinesterase, and Butyrylcholinesterase. PCB showed strong affinities toward BChE (-10.0 kcal/mol) and GSK-3β (-8.4 kcal/mol), suggesting modulation of tauopathic and late-stage cholinergic pathways. P2 exhibited notable binding to AChE (-8.8 kcal/mol) and BACE1 (-7.6 kcal/mol), indicating effects on amyloidogenic and early cholinergic mechanisms, while P1 and P3 provided complementary moderate activity. Overall, these findings support further investigation of PBPs as potential sources of bioactive compounds for functional food and nutraceutical applications targeting AD-related pathways.

Bipolar disorder is a mental illness that causes people to have periods of mania and depression. The dopamine D2 receptor (D2DR), which modulates dopamine levels and is essential for the reward system, mood stabilization, and motivation, along with the serotonin 5-HT2A receptor (HT2AR), which significantly influences mood stability, cognitive function, and anxiety responses via serotonergic signaling, are crucial in bipolar disorder. It was studied the potential interactions of Allium sativum L. chemicals with the dopamine D2 receptor and serotonin 5-HT2A receptor by in silico approaches. This study suggests that the bioactive compounds found in A. sativum L. may exhibit binding affinity toward the dopamine D2 receptor. In contrast, considerably lower binding affinities were observed toward the serotonin 5-HT2A receptor. Their predicted binding characteristics toward the dopamine D2 receptor are reported for the first time. According to findings, especially N-trans-feruloyltramine possesses a structurally stable binding affinity for the dopamine D2 receptor and may represent a computationally prioritized ligand for future experimental investigation concentrating on dopaminergic signaling. Further experimental studies are required to validate these computational findings.

The isatin scaffold has emerged as a promising platform for the development of anticancer agents, as evidenced by several clinically relevant isatin-based compounds. In this study, 85 novel isatin derivatives were designed based on literature reports and evaluated using drug-likeness prediction, ADME profiling, molecular docking, and molecular dynamics simulations. The compounds were screened against VEGFR-2, EGFR, and caspase-6 to identify potential multi-target lead candidates. Based on their binding affinity and pharmacokinetic properties, 41 compounds were shortlisted for further evaluation. Among them, compound 4 exhibited the most favorable binding profile and stable interactions with the selected targets. These findings suggest that compound 4 represents a promising lead for further investigation. However, experimental studies, including enzyme inhibition, cell-based assays, and in vivo evaluation, are required to validate its therapeutic potential. Overall, this study highlights the usefulness of computational approaches in the discovery of novel isatin-based multi-target lead candidates for cancer therapy.

Cardiovascular diseases are the major cause of death worldwide. Atherosclerosis is a chronic inflammatory condition characterized by the accumulation of atherosclerotic plaques in the artery walls of medium and large arteries. Receptor-interacting protein kinase 3 (RIPK3) plays a major role in the development and instability of atherosclerotic plaque. Targeting RIPK3 is a promising therapeutic approach, as current inhibitors have reported side effects and lack specificity. In order to identify new and targeted RIPK3 inhibitors, this study focused on computational approach using methods such as virtual screening with essential descriptors such as drug-likeness and pharmacokinetic properties and docking studies. Three top compounds viz. ZINC96307758, ZINC96136342 and ZINC40012267 were identified that exhibit better binding scores compared to the reference inhibitor GSK843. Further analysis using density functional theory showed that the top compound was more reactive and stable compared to GSK843. The two complexes RIPK3-ZINC40012267 and RIPK3-ZINC96307758 showed the best stability, based on molecular dynamics simulations, as shown by its favorable free energy landscape and low RMSD and RMSF values. Strong binding free energy for the top hits was validated by MMPBSA calculations. Our results point to ZINC40012267 and ZINC96307758 as a particularly strong and stable RIPK3 inhibitor candidate, wet bench experimental validations are required to establish this finding.

A mathematical model is described that enables calculation of drug concentration gradients within structured tissues for high affinity molecules that are taken up by cells. Access of drugs to the complete tissue mass may be prevented by high affinity binding, receptor re-binding, avid permeation into the cell and restricted diffusion (high tissue tortuosity). Varying parameters such as affinity and kinetic constants (association and dissociation rate constants) may be a strategy to manipulate affinity and penetration into structured tissues.

The chemokine receptor type 5 (CCR5) plays a crucial role in HIV-1 entry into host cells, making it a key therapeutic target. This study aimed to identify novel CCR5 inhibitors through pharmacophore-guided virtual screening and molecular dynamics (MD) simulations using ZINC-derived compounds. The 3D structure of CCR5 (PDB ID: 4MBS) was used as the target receptor. A ligand-based pharmacophore model was generated using the Pharmit server, with Maraviroc as a reference molecule. Virtual screening of ZINC compounds was conducted based on pharmacophore features and Lipinski's Rule of Five. The top 10 compounds were subjected to molecular docking, ADMET analysis, and MD simulations using GROMACS to evaluate stability and binding dynamics. Among all screened ligands, ZINC000000867238 exhibited the strongest binding affinity (-10.0 kcal/mol), forming hydrogen bonds with Tyr251 and Glu283, and hydrophobic interactions with Trp86, Phe182, and Tyr108. The compound demonstrated favorable ADMET characteristics, including high absorption, non-mutagenicity, and absence of hERG inhibition. MD simulation confirmed its stability, with RMSD fluctuations between 0.20-0.38 nm, low RMSF deviations in active site residues, and a compact radius of gyration (∼2.48 nm) compared to apo-CCR5. The integrated computational approach identified ZINC000000867238 as a potent and stable CCR5 inhibitor candidate, warranting further in vitro and in vivo validation as a potential HIV-1 entry blocker.

Voltage-gated sodium channels (VGSCs; Nav1.1-Nav1.9) are necessary for the initiation and propagation of action potentials in neurons, cardiac muscle and skeletal muscle. Because of their functional importance, VGSCs have become promising candidates for drug development in the brain, heart, and pain. The aim of this review is to highlight the structure, physiological role and pathological involvement of VGSCs in several different diseases, such as epilepsy, arrhythmias, chronic pain and cancer. Clinically established VGSC-targeting drugs are discussed, as well as recent evidence that shows an involvement of VGSCs in tumor progression and metastasis. Lack of selectivity, blood-brain barrier penetration, and regulatory complexities are among the challenges faced by VGSC-targeted therapy, as discussed in the review. Other challenges with VGSC-targeted therapy, such as high isoform homology, limited selectivity, blood-brain barrier penetration, and regulatory complexities, are also discussed in the review. In addition, new isoform-specific modulation strategies, innovative drug delivery devices, and new therapeutic approaches are highlighted. In summary, VGSCs are interesting but complex therapeutic targets, and future progress in selective targeting and drug delivery will likely increase their potential use across a variety of neurological, cardiovascular, and oncological disorders.