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In Vitro and MD Simulation Study to Explore Physicochemical Parameters for Antibacterial Peptide to Become Potent Anticancer Peptide.

ABSTRACT: Although the physicochemical properties of antimicrobial peptides (AMPs) and anticancer peptides (ACPs) are very similar, it remains unclear which specific parameter(s) of ACPs confer the major anticancer activity. By answering how to construct a short AMP/ACP that could easily be synthesized in the most cost effective way plus conferring a maximum anticancer effect is a very important scientific breakthrough in the development of protein/peptide drugs. In this study, an 18-amino-acids antimicrobial peptide, AcrAP1 (named AP1-Z1), was used as a template. Bioinformatics algorithms were then performed to design its six mutants (AP1-Z3a, AP1-Z3b, AP1-Z5a, AP1-Z5b, AP1-Z7, and AP1-Z9). After a series of in vitro experiments plus intensive computational analysis, the data demonstrated that AP1-Z5a and AP1-Z5b induced both apoptosis and anti-angiogenic effects to achieve the maximum anticancer activity. Specifically, the most effective mutant, AP1-Z5b, exhibited high selectivity for the charged membrane in molecular dynamics simulations. These findings clearly demonstrated that both charge and hydrophobicity play an important role and are necessary to reach an optimum equilibrium for optimizing the anticancer activity of AMPs. Overall, the present study provides a very crucial theoretical basis and important scientific evidence on the key physicochemical parameters of ACP drugs development.

SUBMITTER: Ma R

PROVIDER: S-EPMC6940675 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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<i>In Vitro</i> and MD Simulation Study to Explore Physicochemical Parameters for Antibacterial Peptide to Become Potent Anticancer Peptide.

Ma Rui R Wong Sin Wa SW Ge Lilin L Shaw Chris C Siu Shirley W I SWI Kwok Hang Fai HF

Molecular therapy oncolytics 20191210

Although the physicochemical properties of antimicrobial peptides (AMPs) and anticancer peptides (ACPs) are very similar, it remains unclear which specific parameter(s) of ACPs confer the major anticancer activity. By answering how to construct a short AMP/ACP that could easily be synthesized in the most cost effective way plus conferring a maximum anticancer effect is a very important scientific breakthrough in the development of protein/peptide drugs. In this study, an 18-amino-acids antimicro ...[more]

PMID: 31909181

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Project description:Honey is an attractive natural product with various health benefits. A few honey-based commercial products have successfully been adopted in clinics to improve wound healing. However, screening of other potential sources of medical-grade honey, in particular, honeys from territories with high floral species diversity and high endemicity, is highly needed. The goal of this study was to characterise the physicochemical and antibacterial properties of New Caledonian honey samples (n = 33) and to elucidate the major mechanism of their antibacterial action. Inhibitory antibacterial activity of honeys against Staphylococcus aureus and Pseudomonas aeruginosa was determined with a minimum inhibitory concentration (MIC) assay. Enzymatic activity of glucose oxidase and the content of hydrogen peroxide (H2O2) in honey samples were analysed. Furthermore, total protein content of honeys together with their electrophoretic protein profiles were also determined in the study. The antibacterial efficacy of 24% of the tested honey samples was slightly superior to that of manuka honey with unique manuka factor 15+. The antibacterial activity of catalase-treated honey sample solutions was significantly reduced, suggesting that H2O2 is a key antibacterial compound of diluted honeys. However, the kinetic profiles of H2O2 production in most potent honeys at a MIC value of 6% was not uniform. Under the experimental conditions, we found that a H2O2 concentration of 150 μM in diluted honeys is a critical concentration for inhibiting the growth of S. aureus. In contrast, 150 μM H2O2 in artificial honey solution was not able to inhibit bacterial growth, suggesting a role of phytochemicals in the antibacterial activity of natural honey. In addition, the continuous generation of H2O2 in diluted honey demonstrated an ability to counteract additional bacteria in re-inoculation experiments. In conclusion, the tested New Caledonian honey samples showed strong antibacterial activity, primarily based on H2O2 action, and therefore represent a suitable source for medical-grade honey.

Project description:BackgroundCOVID-19 is a respiratory illness caused by SARS-CoV-2. Pharmaceutical companies aim to control virus spread through effective drugs. This study investigates chromone compound derivatives' ability to inhibit viral entry and prevent replication.MethodThis study investigated the inhibitory effect of chromone-embedded peptidomimetics and furopyrimidines on 7BZ5 from Severe Acute Respiratory Syndrome CoV-2, Homo sapiens, and 6LU7 from Bat SARS-like CoV using molecular docking. The crystal structure of these proteins was obtained from the Protein Data Bank, and the inhibition site was determined using ligand binding interaction options. The 3D structure was protonated and energetically minimised using MOE software. Chromone derivatives were designed in three dimensions, and their energy was minimised using MOE 2019. The molecular drug-likeness was calculated using SwissADME, Lipinski and Benigni-Bossa's rule, and toxicity was calculated using Toxtree v3.1.0 software. Compounds with pharmacological properties were selected for molecular docking, and interactions were assessed using MOE 2019. MD simulations of Mpro-ch-p complexes were performed to evaluate root mean square fluctuations (RMSF) and measure protein stability.ResultThe pharmacokinetic tests revealed that chromone derivatives of the peptidomimetic family have acceptable pharmacokinetic activity in the human body. Some compounds, such as Ch-p1, Ch-p2, Ch-p6, Ch-p7, Ch-p12, and Ch-p13, have pronounced medicinal properties. Molecular docking revealed high affinity for binding to SARS-CoV-2 protease. Ch-p7 had the highest binding energy, likely due to its inhibitory property. A 10 ns molecular dynamics study confirmed the stability of the protein-ligand complex, resulting in minimal fluctuations in the system's backbone. The MM-GBSA analysis revealed free energies of binding of - 19.54 kcal/mol.ConclusionsThe study investigated the inhibition of viral replication using chromone derivatives, finding high inhibitory effects in the peptidomimetic family compared to other studies.

Dataset Information

In Vitro and MD Simulation Study to Explore Physicochemical Parameters for Antibacterial Peptide to Become Potent Anticancer Peptide.

Publications

<i>In Vitro</i> and MD Simulation Study to Explore Physicochemical Parameters for Antibacterial Peptide to Become Potent Anticancer Peptide.

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