Search Results (5)

Synthetic lethality, involving the simultaneous deactivation of two genes, disrupts cellular functions or induces cell death. This study examines its role in cancer, focusing on focal adhesion kinase and Neurofibromin 2. Inhibiting FAK, crucial for synthetic lethality with NF2/Merlin, offers significant cancer treatment potential. No FAK inhibitor has been clinically approved, underscoring the need for new, effective inhibitors. The small-molecule FAK inhibitors identified in this study show promise, with SP docking, IFD, QPLD, and MD simulations revealing intricate interactions. Based on the comprehensive analysis, the MM/GBSA scores from SP docking for amprenavir, bosutinib, ferric derisomaltose, flavin adenine dinucleotide, lactulose, and tafluprost were determined as −72.81, −71.84, −76.70, −69.09, −74.86, and −65.77 kcal/mol, respectively. The MMGBSA results following IFD docking MD identified the top-performing compounds with scores of −84.0518, −75.2591, −71.8943, −84.2638, −56.3019, and −75.3873 kcal/mol, respectively. The MMGBSA results from QPLD docking MD identified the leading compounds with scores of −77.8486, −69.5773, −71.9171, N/A, −62.5716, and −66.8067 kcal/mol, respectively. In conclusion, based on the MMGBSA scores obtained using the three docking methods and the 100 ns MD simulations, and considering the combined evaluation of these methods, amprenavir, ferric derisomaltose, and bosutinib are proposed as the most promising candidates. Full article

SARS-CoV-2 exploits the homotrimer transmembrane Spike glycoproteins (S protein) during host cell invasion. The Omicron XBB subvariant, delta, and prototype SARS-CoV-2 receptor-binding domain show similar binding strength to hACE2 (human Angiotensin-Converting Enzyme 2). Here we utilized multiligand virtual screening to identify small molecule inhibitors for their efficacy against SARS-CoV-2 virus using QPLD, pseudovirus ACE2 Inhibition -Time Resolved Forster/Fluorescence energy transfer (TR-FRET) Assay Screening, and Molecular Dynamics simulations (MDS). Three hundred and fifty thousand compounds were screened against the macrodomain of the nonstructural protein 3 of SARS-CoV-2. Using TR-FRET Assay, we filtered out two of 10 compounds that had no reported activity in in vitro screen against Spike S1: ACE2 binding assay. The percentage inhibition at 30 µM was found to be 79% for “Compound F1877-0839” and 69% for “Compound F0470-0003”. This first of its kind study identified “FILLY” pocket in macrodomains. Our 200 ns MDS revealed stable binding poses of both leads. They can be used for further development of preclinical candidates. Full article

As a member of the class I PI3K family, phosphoinositide 3-kinase δ (PI3Kδ) is an important signaling biomolecule that controls immune cell differentiation, proliferation, migration, and survival. It also represents a potential and promising therapeutic approach for the management of numerous inflammatory and autoimmune diseases. We designed and assessed the biological activity of new fluorinated analogues of CPL302415, taking into account the therapeutic potential of our selective PI3K inhibitor and fluorine introduction as one of the most frequently used modifications of a lead compound to further improve its biological activity. In this paper, we compare and evaluate the accuracy of our previously described and validated in silico workflow with that of the standard (rigid) molecular docking approach. The findings demonstrated that a properly fitted catalytic (binding) pocket for our chemical cores at the induced-fit docking (IFD) and molecular dynamics (MD) stages, along with QM-derived atomic charges, can be used for activity prediction to better distinguish between active and inactive molecules. Moreover, the standard approach seems to be insufficient to score the halogenated derivatives due to the fixed atomic charges, which do not consider the response and indictive effects caused by fluorine. The proposed computational workflow provides a computational tool for the rational design of novel halogenated drugs. Full article

Currently, G protein-coupled receptors (GPCRs) constitute a significant group of membrane-bound receptors representing more than 30% of therapeutic targets. Fluorine is commonly used in designing highly active biological compounds, as evidenced by the steadily increasing number of drugs by the Food and Drug Administration (FDA). Herein, we identified and analyzed 898 target-based F-containing isomeric analog sets for SAR analysis in the ChEMBL database—F_iSAR sets active against 33 different aminergic GPCRs comprising a total of 2163 fluorinated (1201 unique) compounds. We found 30 F_iSAR sets contain activity cliffs (ACs), defined as pairs of structurally similar compounds showing significant differences in affinity (≥50-fold change), where the change of fluorine position may lead up to a 1300-fold change in potency. The analysis of matched molecular pair (MMP) networks indicated that the fluorination of aromatic rings showed no clear trend toward a positive or negative effect on affinity. Additionally, we propose an in silico workflow (including induced-fit docking, molecular dynamics, quantum polarized ligand docking, and binding free energy calculations based on the Generalized-Born Surface-Area (GBSA) model) to score the fluorine positions in the molecule. Full article

Malolactic fermentation (MLF) is responsible for the decarboxylation of l-malic into lactic acid in most red wines and some white wines. It reduces the acidity of wine, improves flavor complexity and microbiological stability. Despite its industrial interest, the MLF mechanism is not fully understood. The objective of this study was to provide new insights into the role of pH on the binding of malic acid to the malolactic enzyme (MLE) of Oenococcus oeni. To this end, sequence similarity networks and phylogenetic analysis were used to generate an MLE homology model, which was further refined by molecular dynamics simulations. The resulting model, together with quantum polarized ligand docking (QPLD), was used to describe the MLE binding pocket and pose of l-malic acid (MAL) and its l-malate (−1) and (−2) protonation states (MAL⁻ and MAL²⁻, respectively). MAL²⁻ has the lowest ∆G_binding, followed by MAL⁻ and MAL, with values of −23.8, −19.6, and −14.6 kJ/mol, respectively, consistent with those obtained by isothermal calorimetry thermodynamic (ITC) assays. Furthermore, molecular dynamics and MM/GBSA results suggest that only MAL²⁻ displays an extended open conformation at the binding pocket, satisfying the geometrical requirements for Mn²⁺ coordination, a critical component of MLE activity. These results are consistent with the intracellular pH conditions of O. oeni cells—ranging from pH 5.8 to 6.1—where the enzymatic decarboxylation of malate occurs. Full article