Lattice structures find application in numerous technological domains, including aerospace and automotive industries for structural components, biomedical sector implants, and heat exchangers. In ...many instances, especially those pertaining to structural applications, fatigue resistance stands as a critical and stringent requirement. The objective of this paper is to advance the analysis of fatigue failure in additively manufactured lattice structures by introducing a predictive fatigue failure model based on the finite element (FE) method and experimentally validating the results. The model utilizes linear homogenization to reduce computational effort in FE simulations. By employing a strain-based parameter, the most critical lattice cell is identified, enabling the prediction of fatigue crack nucleation locations. The Crossland multiaxial fatigue failure criterion is employed to assess the equivalent stress, furnishing the fatigue limit threshold essential for predicting component failure. Inconel 625 specimens are manufactured via the laser-based powder bed fusion of metals additive manufacturing process. In order to validate the model, cantilevers comprising octa-truss lattice cells in both uniform and graded configurations undergo experimental testing subjected to bending loads within the high cycle fatigue regime. The proposed methodology effectively forecasts the location of failure in seventeen out of eighteen samples, establishing itself as a valuable tool for lattice fatigue analysis. Failure consistently manifests in sections of uniform and graded lattice structures characterized by the maximum strain tensor norm. The estimated maximum force required to prevent fatigue failure in the samples is 20 N, based on the computed Crossland equivalent stress.
Chemokine (C–C motif) receptor‐like 2 (CCRL2), is a seven transmembrane receptor closely related to the chemokine receptors CCR1, CCR2, CCR3, and CCR5. Nevertheless, CCRL2 is unable to activate ...conventional G‐protein dependent signaling and to induce cell directional migration. The only commonly accepted CCRL2 ligand is the nonchemokine chemotactic protein chemerin (RARRES2). The chemerin binding to CCLR2 does induce leukocyte chemotaxis, yet, genetic targeting of CCRL2 was shown to modulate the inflammatory response in different experimental models. This mechanism was shown to be crucial for lung dendritic cell migration, neutrophil recruitment, and Natural Killer cell‐dependent immune surveillance in lung cancer. To gain more insight in the interactions involved in the CCRL2‐chemerin, the binding complexes were generated by protein–protein docking, then submitted to accelerated molecular dynamics. The obtained trajectories were inspected by principal component analyses followed by kernel density estimation to identify the ligand‐receptor regions most frequently involved in the binding. To conclude, the reported analyses led to the identification of the putative hot‐spot residues involved in CCRL2‐chemerin binding.
Computational approaches have been increasingly applied to drug design over the past three decades and have already provided some useful results in the discovery of anticancer drugs. Given the ...increased availability of crystal structures in recent years, a growing number of molecular modeling studies on tubulin have been reported. Herein we present a brief overview of the role played by computational methods in anti-tubulin research, specifically in the context of colchicine binding agent research. An overview of current structures is reported, along with a brief discussion on the issues associated with the various tubulin isotypes. Finally, a summary of the most recent and relevant results is presented, highlighting the challenges and opportunities faced by researchers in this field.
Arylthioindoles (ATIs) that possess a 3-methoxyphenylthio or a 3,5-dimethoxyphenylthio moiety at position 2 of the indole ring were effective tubulin assembly inhibitors, but weak inhibitors of MCF-7 ...cell growth. ATIs bearing a 3-(3,4,5-trimethoxyphenyl)thio moiety were potent tubulin polymerization inhibitors, with IC50s in the 2.0 (35) to 4.5 (37) μM range. They also inhibited MCF-7 cell growth at nanomolar concentrations. The 3,4,5-trimethoxy substituted ATIs showed potencies comparable to those of the reference compounds colchicine and combretastatin A-4 in both tubulin assembly and cell growth inhibition assays. Dynamics simulation studies correlate well with the observed experimental data. Furthermore, from careful analysis of the biological and in silico data, we can now hypothesize a basic pharmacophore for this class of compounds.
: KDM5 enzymes are H3K4 specific histone demethylases involved in transcriptional regulation and DNA repair. These proteins are overexpressed in different kinds of cancer, including breast, prostate ...and bladder carcinomas, with positive effects on cancer proliferation and chemoresistance. For these reasons, these enzymes are potential therapeutic targets.
: In the present study, we analyzed the effects of three different inhibitors of KDM5 enzymes in MCF-7 breast cancer cells over-expressing one of them, namely KDM5B/JARID1B. In particular we tested H3K4 demethylation (western blot); radio-sensitivity (cytoxicity and clonogenic assays) and damage accumulation (COMET assay and kinetics of H2AX phosphorylation).
: we show that all three compounds with completely different chemical structures can selectively inhibit KDM5 enzymes and are capable of increasing sensitivity of breast cancer cells to ionizing radiation and radiation-induced damage.
: These findings confirm the involvement of H3K4 specific demethylases in the response to DNA damage, show a requirement of the catalytic function and suggest new strategies for the therapeutic use of their inhibitors.
New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at ...submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.
We designed and synthesized 21 new indolylarylsulfones (IASs) as new HIV-1 NNRTIs. Among these, IAS 12 exhibited a remarkable antiviral activity against single and double mutants (K103N EC50 = ...<0.7 nM; Y181C EC50 = <0.7 nM; Y188L EC50 = 21.3 nM; K103N–Y181C EC50 = 6.2 nM), resulting equally or more active than previuosly reported IAS 6 and some approved anti-HIV-1 drugs. Docking and molecular dynamics simulations of compound 12 in complex with WT, Y181C, Y188L, K103N and K103N–Y181C RTs clarified a general binding mode that was consistent with biological results. Kinetic experiments disclosed that derivative 12 preferentially binds WT and K103N–Y181C RTs to binary and ternary complexes, respectively.
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•We designed and synthesized 21 new indolylarylsulfones (IASs) as new HIV-1 NNRTIs.•IAS 12 exhibited a remarkable antiviral activity against K103N–Y181C mutant strain.•Binding mode of IAS 12 was consistent with biological data.•IAS 12 was able to bind K103N–Y181C RT to ternary complex.
The interaction between proteins is a fundamental event for cellular life that is generally mediated by specialized protein domains or modules. PDZ domains are the largest class of protein-protein ...interaction modules, involved in several cellular pathways such as signal transduction, cell-cell junctions, cell polarity and adhesion, and protein trafficking. Because of that, dysregulation of PDZ domain function often causes the onset of pathologies, thus making this family of domains an interesting pharmaceutical target. In this review article we provide an overview of the structural and functional features of PDZ domains and their involvement in the cellular and molecular pathways at the basis of different human pathologies. We also discuss some of the strategies that have been developed with the final goal to hijack or inhibit the interaction of PDZ domains with their ligands. Because of the generally low binding selectivity of PDZ domain and the scarce efficiency of small molecules in inhibiting PDZ binding, this task resulted particularly difficult to pursue and still demands increasing experimental efforts in order to become completely feasible and successful in vivo.
We synthesized new indolylarylsulfone (IAS) derivatives carrying a heterocyclic tail at the indole-2-carboxamide nitrogen as potential anti-HIV/AIDS agents. Several new IASs yielded EC50 values <1.0 ...nM against HIV-1 WT and mutant strains in MT-4 cells. The (R)-11 enantiomer proved to be exceptionally potent against the whole viral panel; in the reverse transcriptase (RT) screening assay, it was remarkably superior to NVP and EFV and comparable to ETV. The binding poses were consistent with the one previously described for the IAS non-nucleoside reverse transcriptase inhibitors. Docking studies showed that the methyl group of (R)-11 points toward the cleft created by the K103N mutation, different from the corresponding group of (S)-11. By calculating the solvent-accessible surface, we observed that the exposed area of RT in complex with (S)-11 was larger than the area of the (R)-11 complex. Compounds 6 and 16 and enantiomer (R)-11 represent novel robust lead compounds of the IAS class.
Several arylthioindoles had excellent activity as inhibitors both of tubulin polymerization and of the growth of MCF-7 human breast carcinoma cells. Methyl ...3-(3,4,5-trimethoxyphenyl)thio-5-methoxy-1H-indole-2-carboxylate (21), the most potent derivative, showed IC50 = 2.0 μM, 1.6 times more active than colchicine and about as active as combretastatin A-4 (CSA4). Compound 21 inhibited the growth of the MCF-7 cells at IC50 = 13 nM. Colchicine and CSA4 had 13 nM and 17 nM IC50 values, respectively, with these cells.
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