REVIEW Knowledge-based computational methods for identifying or designing novel, non-homologous antimicrobial peptides Davor Juretic ´ • Damir Vukic ˇevic ´ • Draz ˇen Petrov • Mario Novkovic ´ • Viktor Bojovic ´ • Bono Luc ˇic ´ • Nada Ilic ´ • Alessandro Tossi Received: 9 October 2010 / Revised: 16 December 2010 / Accepted: 4 January 2011 / Published online: 28 January 2011 Ó European Biophysical Societies’ Association 2011 Abstract We describe computational approaches for identifying promising lead candidates for the development of peptide antibiotics, in the context of quantitative struc- ture–activity relationships (QSAR) studies for this type of molecule. A first approach deals with predicting the selectivity properties of generated antimicrobial peptide sequences in terms of measured therapeutic indices (TI) for known antimicrobial peptides (AMPs). Based on a training set of anuran AMPs, the concept of sequence moments was used to construct algorithms that could predict TIs for a second test set of natural AMPs and could also predict the effect of point mutations on TI values. This approach was then used to design peptide antibiotics (adepantins) not homologous to known natural or synthetic AMPs. In a second approach, many novel putative AMPs were identi- fied from DNA sequences in EST databases, using the observation that, as a rule, specific subclasses of highly conserved signal peptides are associated exclusively with AMPs. Both anuran and teleost sequences were used to elucidate this observation and its implications. The pre- dicted therapeutic indices of identified sequences could then be used to identify new types of selective putative AMPs for future experimental verification. Keywords Antimicrobial peptides Á Design Á Computational Á Therapeutic index Á Signal peptides Introduction Antimicrobial peptides (AMPs) isolated from many differ- ent species can be considered peptide antibiotics as their cytotoxic activity is significantly lower against host cells than against pathogens (Zasloff 2002). This high selectivity, a mechanism of action which is predominantly non-stereo- specific, and their activity against multidrug-resistant pathogens make them promising lead compounds for drug development (Hancock and Lehrer 1998; Glukhov et al. 2005; Marr et al. 2006). Consequently, many laboratories have been engaged in research related to this new class of antibiotics, little known to clinicians, over the past two decades (Hancock and Sahl 2006; Bommarius and Kalman 2009; Zhang and Falla 2010). To date, no AMP has been approved by the FDA due to a combination of factors including high production costs, low bioavailability, Membrane-active peptides: 455th WE-Heraeus-Seminar and AMP 2010 Workshop. D. Juretic ´(&) Á N. Ilic ´ Department of Physics, Faculty of Science, University of Split, 21000 Split, Croatia e-mail: juretic@pmfst.hr D. Vukic ˇevic ´ Department of Mathematics, Faculty of Science, University of Split, 21000 Split, Croatia D. Petrov Laboratory of Computational Biophysics, Campus Vienna Biocenter 5, 1030 Vienna, Austria M. Novkovic ´ Mediterranean Institute for Life Sciences, 21000 Split, Croatia M. Novkovic ´ Interdisciplinary Centre for Advanced Science and Technology, University of Split, 21000 Split, Croatia V. Bojovic ´ Á B. Luc ˇic ´ Rud¯er Bos ˇkovic ´ Institute, 10000 Zagreb, Croatia A. Tossi Department of Life Sciences, University of Trieste, 34127 Trieste, Italy 123 Eur Biophys J (2011) 40:371–385 DOI 10.1007/s00249-011-0674-7