Effective cisplatin delivery requires a balance between drug loading and retention within the carrier. Here, density functional theory, grand canonical Monte Carlo, and molecular dynamics simulations were combined to investigate how framework chemistry and pore geometry govern cisplatin adsorption in ZIF-8, UiO-66, and Mg-MOF-74. The comparison reveals that retention depends on the spatial organization of adsorption contacts and pore constraints as well as framework–guest attraction. Cooperative interfacial polarization and multipoint anchoring favor local stabilization in ZIF-8, while cage confinement restricts molecular migration. Although ZIF-8 and UiO-66 provide comparable average stabilization of the loaded drug population, the greater mobility in UiO-66 demonstrates the additional role of pore geometry in controlling retention. In Mg-MOF-74, continuous channels support efficient pore filling at high fugacity despite weaker average binding. These findings connect electronic interactions, adsorption-site occupation, and molecular transport within a common structure–property framework. ZIF-8 emerges as a favorable candidate when drug retention is the primary objective, while the contrasting behavior of the three frameworks provides a basis for balancing loading capacity and mobility in MOF-based cisplatin carriers.
Hepatocellular carcinoma (HCC) is an aggressive malignancy driven by epigenetic dysregulation. This study investigates the anticancer potential of sodium propionate (SP) as an epigenetic modulator targeting histone deacetylases (HDACs) using an integrated in silico and in vitro approach. Bioinformatics analyses were conducted using publicly available HCC transcriptomic datasets from GEO database, disease gene database (GeneCards database), and chemical–gene interaction networks (Comparative Toxicogenomic Database) to identify potential therapeutic targets, HDAC2 and HDAC6 as key therapeutic targets in HCC. Computational ADMET screening indicated SP possesses favourable drug-likeness, high oral bioavailability, and low toxicity. Molecular docking and 500-ns molecular dynamics simulations showed stable SP binding to HDAC2, with ligand RMSD of 1.5-2.0 Å, protein RMSD of 3.0-4.5 Å, and active-site RMSF < 1.0 Å, supported by persistent Zn²⁺ coordination and hydrophobic interactions. In vitro evaluations in HepG2 cells revealed distinct dose-dependent cytotoxicity (IC₅₀ = 8.2 mM) and pronounced morphological alterations. Furthermore, SP treatment strongly downregulated the mRNA expression of HDAC2 (0.31-fold, p < 0.001) and HDAC6 (0.60-fold, p < 0.05). This suppression was accompanied by a significant, dose-dependent increase in caspase-3/7 activity, confirming apoptotic induction. These findings suggest SP functions as a dual-action epigenetic modulator in HCC, promoting apoptosis by downregulating HDAC2/6 expression and potentially inhibiting their enzymatic activity. However, biochemical assays, protein-level validation, and in vivo HCC models are necessary to validate this inhibition.
Proteins are known to play multifunctional role including transportation, storage, structural support among others. Among the proteins, hemoglobin (Hb) is known to transport oxygen and binds with many xenobiotics and therapeutic drugs. But, in this paper, the binding of human hemoglobin (HHb) with Ivermectin (IVM) that is a broad-spectrum antiparasitic agent used during COVID-19 pandemic has been presented. Multi-spectroscopic experimental techniques and in-silico docking methods have been used for the intended study. IVM quenched HHb fluorescence via a dynamic quenching process with a quenching constant (Ksv) on the order of 105 M− 1. TCSPC studies confirmed the dynamic quenching by showing a decrease in the lifetime of the fluorophore (HHb) in presence of IVM. The binding affinity (Kb) from UV-Vis and fluorescence studies was on the order of 105 M− 1. The binding constant was observed to increase with rise in temperature. Thermodynamic parameters of the interaction (ΔG⁰, ΔH⁰, ΔS⁰) indicated a spontaneous binding process with negative free energy changes and an entropy driven process due to T∆S0 > ∆H0. A positive value of both enthalpy (ΔH⁰) and entropy (ΔS⁰) changes accompanying the binding showed the driving role of hydrophobic forces in the interaction. Synchronous fluorescence results revealed no considerable changes in the microenvironment of tryptophan (Trp) and tyrosine (Tyr). A visible conformational variation in the secondary structure of HHb especially the α-helix was evident from 3D-fluorescence and circular dichroism (CD) studies. Theoretical docking studies showed the binding site of IVM in the central cavity of HHb. The limitation of this study includes the lack of molecular dynamics simulations to model real-time stability of the complex.
Dermatophytic infections remain a persistent therapeutic challenge, particularly due to the increasing resistance to conventional antifungal agents. In search of alternative antifungal scaffolds, a series of 2-pyridyl–imine derivatives (PYE1–PYE11) was synthesized and evaluated for antimicrobial, cytotoxic, and biomolecular interaction properties. All compounds exhibited antimicrobial activity, with the ortho-vanillin derivative PYE10 showing the highest potency, including remarkable activity against Proteus mirabilis (MIC = 0.01 mg/mL) and Trichophyton mentagrophytes (MIC = 0.05 mg/mL). Fluorescence displacement assays provided evidence for PYE10–DNA interactions involving both intercalative and minor-groove-associated binding modes, while human serum albumin binding studies revealed 1:1 complex formation, indicating appreciable interaction with HSA. Molecular docking and molecular dynamics simulations identified favorable and stable binding of the most active compounds within the CYP51B active site, supporting the experimentally observed antifungal activity. Computational thermodynamic analysis indicated that Fe2⁺ chelation is protonation-dependent under physiological conditions. Structure–activity relationship analysis revealed that antimicrobial activity is influenced by the electronic nature of substituents, aromatic planarity, molecular flexibility, and the ability to establish multiple intermolecular interactions. In silico ADMET evaluation demonstrated favorable drug-likeness and pharmacokinetic profiles, highlighting these pyridyl–imine derivatives as promising candidates for further antimicrobial development.
A new approach for the prioritized hit compound optimization directions at the hit-to-lead (H2L) stage is proposed in this study. The high variability in the level of expert assessment among researchers and inefficient resource management during the H2L stage exert a strong influence on the success probability of the overall drug discovery process, which highlights the demand of implementing decision support systems (DSS) designed to integrate the advantages of various commonly accepted practices. Within the framework of the study, an algorithm was developed that combines methods of structure-based drug design (SBDD) with a reverse fragment-based drug design (R-FBDD) approach, allowing for the formation of rationalized recommendations for hit molecule growth directions based on the analysis of fragment contributions to the binding energy and the estimation of fragment group efficiency (GE). Retrospective application of the method to a series of Notum carboxylesterase inhibitors demonstrated a good correlation between the prioritized growth vectors proposed by the algorithm and the experimentally implemented H2L optimization strategies, confirming the potential of the proposed approach as a decision support tool at the hit compound optimization stage.
