Computer-aided approaches reveal trihydroxychroman and pyrazolone derivatives as potential inhibitors of SARS-CoV-2 virus main protease

COVID-19 was declared a pandemic by the World Health Organization (WHO) in March 2020. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this study is to target the SARS-CoV-2 virus main protease (Mpro) via structure-based virtual screening. Consequently, > 580,000 ligands were processed via several filtration and docking steps, then the top 21 compounds were analysed extensively via MM-GBSA scoring and molecular dynamic simulations. Interestingly, the top compounds showed favorable binding energies and binding patterns to the protease enzyme, forming interactions with several key residues. Trihydroxychroman and pyrazolone derivatives, SN02 and SN18 ligands, exhibited very promising binding modes along with the best MM-GBSA scoring of –40.9 and –41.2 kcal mol–1, resp. Hence, MD simulations for the ligand-protein complexes of SN02 and SN18 affirmed the previously attained results of the potential inhibition activity of these two ligands. These potential inhibitors can be the starting point for further studies to pave way for the discovery of new antiviral drugs for SARS-CoV-2

Computer-aided discovery of antimicrobial agents as potential enoyl acyl carrier protein reductase inhibitors

Purpose: To perform a virtual screening for a set of drug-like ligand library against the Staphylococcus aureus enoyl acyl carrier protein reductase, saFabI.Methods: The virtual screening was conducted based on a previously validated pharmacophoreconstrained docking. Consequently, the top list obtained was filtered using visual inspection where forty compounds were selected for experimental testing using disk-diffusion test and broth dilution method. The hits obtained were checked for their toxicity against human fibroblasts cell lines.Results: Three compounds were active against Staphylococcus aureus and other tested gram-positive bacteria. However, no significant inhibitory activity (p < 0.05) was detected against Escherichia coli or Candida albicans. The minimum inhibitory concentration (MIC) values for the most active compounds were identified using the broth dilution method; all of them exhibited inhibitory activity within micromolar range.The docking results showed that the hits obtained exhibited a small size with a nice binding mode to saFabI enzyme, forming the important interactions with the key residues. Furthermore, the best three hits demonstrated good safety profile as they did not show any significant toxicity against human fibroblast cell line.Conclusion: Overall, the newly discovered hits can act as a good starting point in the future for the development of safe and potent antibacterial agents.Keywords: Enoyl acyl carrier protein reductase, saFabI, Antibacterial agents, Docking, Constraint, Virtual screening Tropical Journal of Pharmaceutica

Inhibition of N1-Src kinase by a specific SH3 peptide ligand reveals a role for N1-Src in neurite elongation by L1-CAM

In the mammalian brain the ubiquitous tyrosine kinase, C-Src, undergoes splicing to insert short sequences in the SH3 domain to yield N1- and N2-Src. We and others have previously shown that the N-Srcs have altered substrate specificity and kinase activity compared to C-Src. However, the exact functions of the N-Srcs are unknown and it is likely that N-Src signalling events have been misattributed to C-Src because they cannot be distinguished by conventional Src inhibitors that target the kinase domain. By screening a peptide phage display library, we discovered a novel ligand (PDN1) that targets the unique SH3 domain of N1-Src and inhibits N1-Src in cells. In cultured neurons, PDN1 fused to a fluorescent protein inhibited neurite outgrowth, an effect that was mimicked by shRNA targeting the N1-Src microexon. PDN1 also inhibited L1-CAM-dependent neurite elongation in cerebellar granule neurons, a pathway previously shown to be disrupted in Src(−/−) mice. PDN1 therefore represents a novel tool for distinguishing the functions of N1-Src and C-Src in neurons and is a starting point for the development of a small molecule inhibitor of N1-Src

Design, synthesis and evaluation of inhibitors for Src tyrosine kinase and their impact on colorectal cancer cells

Colorectal cancer is the highest cause of cancer-related death in the West. c-Src protein levels are elevated in colon cancer cells compared to non-malignant cells, In addition, Src signalling and transduction are directly involved in cell growth, cell cycle, malignant transformation and cell migration, providing opportunities for inhibition of Src.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Design, synthesis and evaluation of inhibitors for Src tyrosine kinase and their impact on colorectal cancer cells

Colorectal cancer is the highest cause of cancer-related death in the West. c-Src protein levels are elevated in colon cancer cells compared to non-malignant cells, In addition, Src signalling and transduction are directly involved in cell growth, cell cycle, malignant transformation and cell migration, providing opportunities for inhibition of Src.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Characterization of T1InS1.8Se0.2 as advanced functional crystals

In this work, selenium doped TlInS1.8Se0.2 crystals are used to fabricate multifunctional devices that can handle more than one duty at a time. After revealing the morphological, compositional, structural and optical properties of the doped crystal, it is sandwiched between Ag and carbon metals. The crystals are characterized by means of ultraviolet-visible light spectrophotometry, impedance spectroscopy and illumination dependent current-voltage characteristics techniques. While the optical spectroscopy allowed determining the energy band gap of the crystals as well as the optical conductivity in the terahertz frequency domain, the impedance spectroscopy allowed identifying the conductance and reflectance spectra in the gigahertz frequency domain. The two techniques reveal promising characteristics presented by optical switching at 2.20 eV and band pass filtering properties in mega/gigahertz frequency domains. On the other hand, the analysis of the current (I)- voltage (V) characteristics which are recorded in the dark and under photoexcitation of unfiltered tungsten light in the light power range of 25-130 mW, revealed light intensity dependent rectifying properties. Particularly, the modeling of the experimental I-V curves in accordance with the Richardson Schottky and Chueng's theoretical approaches have shown that the Schottky diode ideality factor, series resistance and barrier height decreases with increasing light power. Such behavior indicates wide tunability of the device when used as photosensors. With the features presented by small size, photosensitivity, gigahertz/terahertz spectral responses, the device can be promising element for use in visible light and microwave communications

Druggability analysis and classification of protein tyrosine phosphatase active sites

Mohammad A Ghattas, Noor Raslan, Asil Sadeq, Mohammad Al Sorkhy, Noor Atatreh College of Pharmacy, Al Ain University of Science and Technology, Al Ain, UAE Abstract: Protein tyrosine phosphatases (PTP) play important roles in the pathogenesis of many diseases. The fact that no PTP inhibitors have reached the market so far has raised many questions about their druggability. In this study, the active sites of 17 PTPs were characterized and assessed for its ability to bind drug-like molecules. Consequently, PTPs were classified according to their druggability scores into four main categories. Only four members showed intermediate to very druggable pocket; interestingly, the rest of them exhibited poor druggability. Particularly focusing on PTP1B, we also demonstrated the influence of several factors on the druggability of PTP active site. For instance, the open conformation showed better druggability than the closed conformation, while the tight-bound water molecules appeared to have minimal effect on the PTP1B druggability. Finally, the allosteric site of PTP1B was found to exhibit superior druggability compared to the catalytic pocket. This analysis can prove useful in the discovery of new PTP inhibitors by assisting researchers in predicting hit rates from high throughput or virtual screening and saving unnecessary cost, time, and efforts via prioritizing PTP targets according to their predicted druggability. Keywords: PTP1B, oral bioavailability, drug-like inhibitors, drug design, active site, allosteric site, MPtpB, CD45, SHP2, Yop