Application of 3D-QSAR for Identification of Descriptors Defining Bioactivity of Antimicrobial Peptides

Abstract

In our laboratory, a series of antimicrobial peptides have been developed, where the resulting 3D-physicochemical properties are controlled by the placement of amino acids with well-defined properties (hydrophobicity, charge density, electrostatic potential, and so on) at specific locations along the peptide backbone. These peptides exhibited different in vitro activity against Staphylococcus aureus (SA) and Mycobacterium ranae (MR) bacteria. We hypothesized that the differences in the biological activity is a direct manifestation of different physicochemical interactions that occur between the peptides and the cell membranes of the bacteria. 3D-QSAR analysis has shown that, within this series, specific physicochemical properties are responsible for antibacterial activity and selectivity. There are five physicochemical properties specific to the SA QSAR model, while five properties are specific to the MR QSAR model. These results support the hypothesis that, for any particular AMP, organism selectivity and potency are controlled by the chemical composition of the target cell membrane.

New trends in peptide-based anti-biofilm strategies: a review of recent achievements and bioinformatic approaches

“…Also, QSAR analyses have been used in the production of lactoferricin, bactenecin, and protegrin derivatives , and the optimization of the activity of novispirin G10 (Taboureau et al 2006;Blondelle and Lohner 2010). Moreover, a 3D-QSAR analysis of a series of AMPs (Bhonsle et al 2007;Blondelle and Lohner 2010) revealed that for any particular AMP, cell selectivity and potency are controlled by the chemical composition of the target cell membrane, and a combined approach of atomicresolution QSARs with ANNs Fjell et al 2009;Blondelle and Lohner 2010), applied to a large data set of peptides containing high sequence diversity, has shown that the most potent peptides exhibit a high frequency of the amino acids tryptophan, arginine, lysine, isoleucine and leucine.…”

Effect of Liposome Surface Charge and Peptide Side Chain Charge Density on Antimicrobial Peptide-Membrane Binding as Determined by Circular Dichroism

“…Adopting different conformations on binding to zwiterionic and anionic membrane models is a requirement for organism selectivity. This is because changing the conformation of an AMP changes its amphipathic nature which in turn changes its physicochemical surface properties [27,43]. The changes in the conformation/physicochemical properties of the AMP will lead to different mechanisms of interaction with zwitter ionic and anionic liposomes and thus to organism selectivity [32,[44][45][46].…”

“…This hypothesis is yet to be proven. Compounds 23,43 and 53on binding to 3:1 POPC/POPG exhibited CD spectra (Figure 4) similar in shape, indicating similar binding conformations, however the intensities were different indicating different binding affinities. The intensity of the spectra increased in the order 56<53<23<43.…”

“…The length of the side chain of the basic amino acids (23,43,53) doesn't seem to effect the binding to 3:1 POPC/POPS mixed liposomes since the CD spectra are very similar in periodicity and shape ( Figure 2). However, delocalization of the positive charge of the guanidinium group of compound 56, seems to affect the binding to (Figure 2).…”

The Design of Bacteria Strain Selective Antimicrobial Peptides Based on the Incorporation of Unnatural Amino Acids

“…As the name implies cell selective AMPs exhibit potent activity against bacterial cells while remaining inactive against mammalian cells, non-selective AMPs exhibit activity against bacterial as well as mammalian cells. We have previously reported the synthesis and biological evaluation of a series of potent (low µM to nm in vitro activity, and low acute toxicity 125 mg/kg in mice) bacteria selective membrane disruptors based on the incorporation of three Tic-Oic dipeptide units (Bhonsle, Venugopal, Huddler, Magill, & Hicks, 2007). The in vitro antibacterial activity exhibited by the analogs containing six dipeptide units against seven strains of bacteria is given in Table 2.…”