Metal-based compounds continue to attract considerable attention as bioactive agents due to their versatile coordination behavior and ability to modulate biomolecular structure and function. In this study, a phenolic Schiff base ligand, 2-[(5-methoxy-2-hydroxy-phenylimino)methyl]-4-nitrophenol (MHNP), was utilized to synthesize a series of Ru(III), Zn(II), and VO(II) complexes. The structures of the obtained complexes were elucidated using various spectroscopic techniques, and their stability was evaluated to assess suitability for biological applications. Density functional theory (DFT) calculations were performed to provide molecular-level insight into electronic properties and preferred coordination geometries. The combined experimental and theoretical results indicate that the MHNP ligand coordinates through NOO donor atoms, forming octahedral geometry with Ru(III), tetrahedral geometry with Zn(II), and square pyramidal geometry with VO(II) complexes. DNA interaction studies were conducted to evaluate the binding affinity of the complexes toward double-stranded DNA. The results demonstrate enhanced DNA-binding upon metal coordination, with binding modes dependent on the metal center. Notably, the Ru(III) complex exhibited stronger interactions, suggesting groove-binding or intercalative behavior, while Zn(II) and VO(II) complexes showed moderate but stable binding profiles. Structure–interaction relationships highlight the significant role of metal ions in tuning biomolecular recognition. Additionally, the redox properties of Ru(III) and VO(II), along with the redox-modulating nature of Zn(II), suggest potential antioxidant activity through regulation of reactive oxygen species. Overall, these findings indicate that MHNP-based metal complexes are promising multifunctional candidates for antimicrobial, anticancer, and antioxidant applications, offering a rational basis for the development of metal-based therapeutics.

Inflammation-driven diseases are characterized by localized oxidative stress, acidosis, and hyperthermia—microenvironmental features that often compromise the effectiveness of conventional anti-inflammatory therapies due to poor site selectivity and uncontrolled systemic exposure. In this context, the present study provides an exclusively in silico investigation of an inflammation-responsive drug delivery concept based on β-cyclodextrin (β-CD) encapsulation of a redox-active vanadium complex, VO–INAP–tryptophan. Leveraging the supramolecular host–guest properties of β-CD, the computational model explores a system designed to remain stable under physiological conditions while undergoing selective destabilization within the pathological microenvironment of inflamed tissues. Two plausible inclusion modes of the vanadium complex within the β-CD cavity were systematically evaluated under simulated inflammatory conditions, including acidic pH, increased dielectric constant, and elevated temperature. Frontier molecular orbital analysis and global reactivity descriptors were used to examine how variations in electronic structure, thermodynamic stability, and chemical reactivity influence encapsulation strength and release propensity. The results identify a specific inclusion conformation particularly susceptible to solvent competition and electronic destabilization, indicating a favorable pathway for site-selective release. Component-resolved electronic analysis highlights the complementary roles of the vanadium center and the tryptophan ligand in modulating redox behavior and potential anti-inflammatory activity. Overall, this study provides computational insights that may inform a mechanistic framework for designing inflammation-responsive supramolecular delivery systems and suggests the potential of β-cyclodextrin architectures for optimizing the therapeutic performance of redox-active metal complexes, pending experimental validation.

Non-enzymatic glycation of serum albumin by reducing sugars and reactive carbonyls was implicated in altered ligand transport and protein deposition in metabolic disease, representing a critical molecular link between chronic hyperglycemia and diabetic complications. Here, we employed a Box–Behnken Design (BBD) to systematically vary bovine serum albumin (BSA) concentration (40-50mg), glucose (1-5mg), methylglyoxal (0.4–2 µM), glyoxal (0.4–4 nM), and diacetyl (1–10 nM) in 46 independent experiments. Secondary-structure changes were probed by Fourier-transform infrared spectroscopy (FTIR) via deconvolution of the amide I/II region and by far-UV circular dichroism (CD) at 208 nm and 222 nm. Quadratic response-surface models were constructed for α-helix and β-sheet contributions, achieving R2 values of ∼0.76 (FTIR α-helix), ∼0.81 (FTIR β-sheet), ∼0.69 (CD 208 nm), and ∼0.98 (CD 222 nm). Results revealed that glycation strongly destabilized α-helices, with a-helix content decreasing by up to 27.4% (FTIR) and about 60% (CD @222nm) relative to native BSA control, particularly under combinations of glucose with methylglyoxal or diacetyl, and at intermediate to high BSA concentrations. β-sheet enrichment occurred primarily at high protein concentration and in the presence of dicarbonyl mixtures, indicative of aggregation-prone states. The parallel trends in FTIR and CD confirmed that helical loss preceded and triggered β-sheet formation. These findings provide a quantitative insight into how combinations of glycating agents, not simply glucose alone, govern albumin structural integrity via non-linear, concentration- and chemistry-dependent pathways. Unlike conventional single-variable (one-factor-at-a-time, OFAT) glycation studies, the present multivariate DoE framework captured non-linear and synergistic interactions among glycating agents, and advanced our mechanistic understanding of albumin misfolding under carbonyl stress.

Candida albicans, an opportunistic pathogen, uptakes host-derived carbon sources for its survival and causes candidiasis infection. However, host defences such as macrophages restrict the C. albicans’ sugar uptake via phagocytosis, triggering the glyoxylate pathway for adaptation in nutrient-limited conditions. Within macrophages, the C. albicans malate synthase (CaMLS1) exploits the available acetyl-CoA (ACOA), which condenses in presence of Mg2+ with glyoxylate (GOXL) to form malate, supporting its survival. The absence of structural studies highlights the need for in silico interventions to better understand CaMLS1 functional architecture thereby aiding in design of the therapeutic drug agents. In this study, computational approaches such as MD simulations, correlations studies and binding affinity analysis were employed to delineate the structural dynamics and to investigate the interactions of cofactors and substrates with CaMLS1. From the results, template-based 3D modeling revealed that CaMLS1 has three domains: N-terminal, TIM-barrel and C-terminal domain, of which TIM-barrel found to be dynamic through MD studies. However, substrates (GOXL and ACOA) binding to CaMLS1 markedly reduced this dynamism, indicating the stability of the complex. The binding free energy calculations of the complex showed that ACOA binds with notably higher affinity (−921 kJ/mol) than GOXL (−6 kJ/mol), consistent with previous observations reported in literature. Furthermore, presence of cofactors and substrates modulated the tunnel availability at the active site, thereby affecting substrate’s access and product release through changes in the enzyme’s conformational dynamics. These findings offer a scope for the design of molecules targeting the CaMLS1 for antifungal therapy.

Although treatable, tuberculosis remains a leading cause of death, and multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains have intensified its burden. The serine/threonine kinase G (PknG) of Mycobacterium tuberculosis is an attractive target because it enables immune evasion. More than 100 PknG inhibitors have been reported, yet none has progressed to regulatory approval and explicit design rules are lacking. A comprehensive chemoinformatic analysis was performed on reported PknG inhibitors. Principal component analysis (PCA) was used to explore chemical space. Furthermore, docking studies were used to conduct a structure-activity relationship (SAR) assessment and identify key molecular features associated with enhanced inhibition. Molecular dynamics simulations of representative PknG–inhibitor complexes were then carried out to characterize the stability and persistence of key binding interactions and to compute per-residue binding free energy contributions. Based on these trajectories, hydration analyses using the V4S index were applied to identify regions of the binding site where water removal is energetically favorable, thereby enabling direct ligand–protein interactions. Four interaction regions were identified: the hinge region (HR), catalytic region (CR), core and hydrophobic region (HyR). Engagement of the HR was found essential for binding, while interactions within the CR significantly enhanced inhibitory activity, improving potency by up to one order of magnitude (A9 IC50:0.01 µM vs. AX20017:0.3 µM). These findings define a simple structure-based strategy for designing PknG inhibitors, providing a rule of thumb that, together with computational methods, may guide rational therapeutic development.

Interleukin-2 receptor γ chain (IL2RG, CD132) act as a signaling subunits for various cytokine receptors, required for lymphocyte growth and maturation. Genetic variants within the IL2RG gene are associated with X-linked Severe Combined Immunodeficiency (X-SCID) disease. This study uses an in-silico method to investigate the structural and functional impacts of two IL2RG variants, Trp240Arg (W240R) and Arg226Cys (R226C), located in the extracellular domain, a region important for receptor stability. Homology modeling was generated for Wild–Type (WT) and Variant IL2RG structures and subsequently analyzed through Molecular Dynamics (MD) simulations and protein–protein docking utilizing IL-2 and IL-21 cytokines. MD simulations showed that WT–IL2RG remained stable, whereas its variant exhibited structural instability. W240R is disrupted by increased solvent exposure and reduced compactness. The IL-2 binding caused structural alterations in the WT complex in cytokine-bound states, whereas R226C reduced hydrogen bonds to decrease binding, and W240R increased flexibility to destabilize the interface. The WT complex exhibited consistent hydrogen bonding and was the most stable for IL-21, whereas both variants displayed weaker interactions and fluctuations. Further, the binding free energy Molecular Mechanics-Poisson Boltzmann Surface Area (MM/PBSA) analysis confirmed that WT complexes had better binding (IL-2: −40.87 kJ/mol; IL-21: −45.88 kcal/mol) compared to R226C (-35.42, −34.67 kcal/mol) and W240R (-29.54, −33.30 kcal/mol). The study reveals that Trp240Arg and Arg226Cys variants in IL2RG negatively affect cytokine-receptor interactions, lower binding energetics, and disturb the structural integrity of IL2RG, shedding light on the mechanisms underlying IL2RG-associated immunodeficiency disorders.

Angiotensin-converting enzyme 2 (ACE2) regulates cardiovascular function and serves as the SARS-CoV-2 entry receptor, making it a dual therapeutic target. Most drug development focuses on the virus rather than exploring broader host-directed protective strategies. We hypothesize that imidazopyridine derivatives may serve as candidate ACE2 binders for experimental evaluation with potential applications in both antiviral and cardiovascular contexts. Here, we present an integrated computational study of 67 imidazopyridine derivatives as ACE2 modulators. Molecular docking, MM-GBSA binding free energy calculations, and 100-ns molecular dynamics simulations identified compound 28 as a lead candidate with the highest binding affinity among all tested derivatives (Glide score: −9.97 kcal/mol; MM-GBSA: −79.26 kcal/mol). This compound formed stable interactions with catalytic residues and preserved structural integrity throughout simulations. Principal component analysis revealed three conformational states, indicating that compound 28 maintains stable binding while preserving the conformational flexibility necessary for catalytic function. These results identify imidazopyridines as candidate binders for experimental validation and establish a computational framework to guide future experimental studies of host-directed ACE2 modulators.

The opening of the receptor-binding domain of the SARS-CoV-2 spike (S) glycoprotein is a key conformational change required for viral entry. In this work, we use an integrated computational approach to evaluate how small molecules may allosterically alter this process. From an initial library of ∼ 60,000 ZINC compounds screened using physicochemical, absorption, and spatial criteria, 739 candidates were identified and clustered to select nine representatives to study their allosteric effect on the protein activation (opening). Classical molecular dynamics simulations revealed distinct differences in ligand stability, while steered (non-equilibrium) simulations quantified how each compound affected the opening motion of the receptor-binding domain. Free-energy profiles constructed from umbrella sampling, together with conformational population density maps derived from principal component analysis, showed that small ligands provide limited inhibition, medium-sized ligands produce the most consistent stabilizing effects, and two of the heaviest ligands substantially reshape the activation pathway by stabilizing closed or intermediate conformations. Overall, the presented approach provides a practical screening framework for analyzing the effect of small molecules on large conformational changes in viral fusion proteins allowing the assessment of reaction barriers in nanosecond timescale.

Recent proteomic studies have identified several different lysine modifications in plants related to various important metabolic pathways. Lysine deacylation is a key feature of sirtuins for the regulation of several cellular processes in mammals. A similar mechanism may also be involved in the different stress tolerance in plants. In this study, we deliver a comprehensive structural and kinetic analysis describing the selection of acidic acyl groups for OsCobB as a substrate. The catalytic efficiency (kcat/Km ) of OsCobB to erase glutaryl, succinyl, and malonyl groups from the designated lysine site is favored due to the presence of Tyr55 and Arg58 at the active site. MD simulation analyses further confirm the fact that the selectivity of the substrate is based on the residues lining the OsCobB active site as well as those adjacent to the modified lysine. With each increase in the -CH2 group, the binding energy of the modified peptide with OsCobB also increases. Further, findings in this study suggests a potential role of these modifications in plants responses to cope with stress due to dehydration, cold temperature and metal toxicity.