IN SILICO PHARMACOKINETICS AND MOLECULAR DOCKING OF THREE LEADS ISOLATED FROM TARCONANTHUS CAMPHORATUS L.

Objective: To investigate the pharmacokinetic and toxicity profiles and spectrum of biological activities of three phytochemicals isolated from Tarconanthus camphoratus L. Methods: Several integrated web based in silico pharmacokinetic tools were used to estimate the druggability of Hispidulin, Nepetin and Parthenolide. Afterward, the structural based virtual screening for the three compounds' potential targets was performed using PharmMapper online server. The molecular docking was conducted using Auto-Dock 4.0 software to study the binding interactions of these compounds with the targets predicted by PharmMapper server. Results: The permeability properties for all compounds were found within the limit range stated for Lipinski׳s rule of five. Only Parthenolide proved to be able to penetrate through blood brain barrier. Isopentenyl-diphosphate delta-isomerase (IPPI), uridine-cytidine kinase-2 (UCK-2) and the mitogen-activated protein kinase kinase-1 (MEK-1) were proposed as potential targets for Hispidulin, Nepetin and Parthenolide, respectively. Nepetin and Parthenolide were predicted to have anticancer activities. The activity of Nepetin appeared to be mediated through UCK-2 inhibition. On the other hand, inhibition of MEK-1 and enhancement of TP53 expression were predicted as the anticancer mechanisms of Parthenolide. The three compounds showed interesting interactions and satisfactory binding energies when docked into their relevant targets. Conclusion: The ADMET profiles and biological activity spectra of Hispidulin, Nepetin and Parthenolide have been addressed. These compounds are proposed to have activities against a variety of human aliments such as tumors, muscular dystrophy, and diabetic cataracts.Keywords: Tarconanthus camphoratus L., Hispidulin, Nepetin, Parthenolide, In silico pharmacokinetic, Molecular docking, PharmMapper server, and Auto-Dock 4.0 softwareÂ

Antimicrobial Peptide Synergies for Fighting Infectious Diseases

Abstract Antimicrobial peptides (AMPs) are essential elements of thehost defense system. Characterized by heterogenous structures and broad‐spectrumaction, they are promising candidates for combating multidrug resistance. Thecombined use of AMPs with other antimicrobial agents provides a new arsenal ofdrugs with synergistic action, thereby overcoming the drawback of monotherapiesduring infections. AMPs kill microbes via pore formation, thus inhibitingintracellular functions. This mechanism of action by AMPs is an advantage overantibiotics as it hinders the development of drug resistance. The synergisticeffect of AMPs will allow the repurposing of conventional antimicrobials andenhance their clinical outcomes, reduce toxicity, and, most significantly,prevent the development of resistance. In this review, various synergies ofAMPs with antimicrobials and miscellaneous agents are discussed. The effect ofstructural diversity and chemical modification on AMP properties is firstaddressed and then different combinations that can lead to synergistic action,whether this combination is between AMPs and antimicrobials, or AMPs andmiscellaneous compounds, are attended. This review can serve as guidance whenredesigning and repurposing the use of AMPs in combination with other antimicrobialagents for enhanced clinical outcomes

Novel CA(1-7)M(2-9) Analogs: Synthesis, Characterization, and Antibacterial Evaluation

Hybrid peptides from cecropin A and melittin have attracted the interest of the research community for decades. Here we synthesized several new analogs of the pentadecapeptide CA(1-7)M(2-9) and studied their antibacterial and hemolytic activity and tryptic stability. Single substitution of the Lys residues by Arg did not have a significant impact on the antibacterial activity of these analogs, but the substitution of the five Lys residues by Arg resulted in an increment in hemolytic activity. In contrast, the substitution of Lys residues by Orn conserved the antibacterial activity, with even lower hemolysis, and improved the enzymatic stability. The disulfide cyclic version of CA(1-7)M(2-9) was obtained by adding a Cys residue to each end of the peptide and carrying out a chemoselective thiol-disulfide interchange using sec-isoamylmecaptan as protecting group of one of these residues. This cyclic peptide showed good antibacterial activity with low hemolysis and improved enzymatic stability.We thank Dr. Thomas Bruckdorfer (Iris Biotech GmbH, Marktredwitz, Germany) for encouraging this work and for the generous gift of Fmoc-Cys(SIT)-OH; Jonathan Collins (CEM Corp., Matthews, NC, USA) for facilitating the use of the CEM Liberty Blue microwave peptide synthesizer; and Yoav Luxembourg (Luxembourg Biotechnologies, Ness Ziona, Israel) for a generous gift of coupling reagents. The work was funded in part by Marató TV3 Foundation 2018 (no. 20183530) and the Republic of South Africa’s National Research Foundation Blue Skies Research Programme (no. 120386).Peer reviewe