Utilization of the Monte Carlo Method to Build up QSAR Models for Hemolysis and Cytotoxicity of Antimicrobial Peptides.

BACKGROUND: Traditional quantitative structure - property / activity relationships (QSPRs/QSARs) are based on representation of molecular structure by molecular graph or simplified molecular input-line entry system (SMILES). It is an attractive idea to develop predictive models for large molecules in general and for peptides in particular. However, the representation of these molecules by molecular graph or SMILES is problematic owing to large size of these molecules. A possible alternative of SMILES is the representation of peptides via sequence of abbreviations of amino acids. METHOD: Models for hemolysis and cytotoxicity of peptides are suggested. These models are based on representation of the peptides by sequences of amino acids. Correlation weights, which are calculated for each amino acid using the Monte Carlo method are basis for quantitative sequence - activity relationships (QSAR) for antimicrobial peptides. The correlation weights are the basis for optimal descriptors, which are correlated with experimental data for hemolysis and cytotoxicity. The basic hypothesis is that if optimal descriptors are correlated with endpoints of peptides for the training set, they should also correlate with the endpoints for validation set. RESULTS: Checking up of correlations between the above-mentioned descriptors and antimicrobial activity of peptides (cytotoxicity or hemolysis) has shown that these models have good predictive potential. CONCLUSION: Suggested approach can be used as a tool to develop predictive models of biological activity of peptides as a mathematical function of sequences of amino acids.

Antimicrobial peptides: therapeutic potentials.

The increasing appearance of multidrug-resistant pathogens has created an urgent need for suitable alternatives to current antibiotics. Antimicrobial peptides (AMPs), which act as defensive weapons against microbes, have received great attention because of broad-spectrum activities, unique action mechanisms and rare antibiotic-resistant variants. Despite desirable characteristics, they have shown limitations in pharmaceutical development due to toxicity, stability and manufacturing costs. Because of these drawbacks, only a few AMPs have been tested in Phase III clinical trials and no AMPs have been approved by the US FDA yet. However, these obstacles could be overcome by well-known methods such as changing physicochemical characteristics and introducing nonnatural amino acids, acetylation or amidation, as well as modern techniques like molecular targeted AMPs, liposomal formulations and drug delivery systems. Thus, the current challenge in this field is to develop therapeutic AMPs at a reasonable cost as well as to overcome the limitations.

[Assessment of safety of lyophilized substance of antibacterial peptide complex].

AIM: To assessment acute and chronic toxicity and local irritative effect of antibacterial peptide complex (ABC) substance extracted from interferon preparations. MATERIALS AND METHODS: Preclinical assessment of ABC substance was performed according to "Requirements for preclinical study of overall toxicity of new pharmacological substances". RESULTS: Series of experiments showed that single or prolonged (during 30 days) administration of ABC substance solution to mice intragastrically or rectally in maximal doses did not lead to death of experimental animals or pathological changes in their organs during pathomorphological and histological studies. Assessment of immune system state showed that administration of solution of studied substance during 1 month in dose 25 times higher than therapeutic leaded to stimulation of phagocytic activity of peripheral blood neutrophils. CONCLUSION: Assessment of acute and chronic toxicity showed that substance of ABC synthesized by virus-induced donor leukocytes during interferon synthesis is well tolerated by experimental animals, does not render toxic effects on their organisms, and possesses immunomodulating activity.