Antibacterial peptides modeling

CONTENTS Preface, C. Allen Bush. Thermodynamic Solvent Isotope Effects and Molecular Hydrophobicity, Terrence G. Oas and Eric J. Toone. Membrane Interactions of Hemolytic and Antibacterial Peptides, Karl Lohner and Richard M. Epand. Spin-Labeled Metabolite Analogs as Probes of Enzyme Structure, Chakravarthy Narasimhan and Henry M. Miziorko. Current Perspectives on the Mechanism of Catalysis by the Enzyme Enolase, John M. Brewer and Lukasz Leb-ioda. Protein-DNA Interactions The Papillomavirus E2 Proteins as a Model System, Rashmi S. Hedge. NMR-Based Structure Determination for Unlabeled RNA and DNA, Philip N. Borer, Lucia Pappalardo, Deborah J. Kenwood, and Istvan Pelczer. Evolution of Mononuclear to Binuclear CuA An EPR Study, William E. Antholine. Index. 

There are two separate but interrelated aspects to QSAR modeling of antibacterial peptides the choice of QSAR descriptors and the choice of numerical analysis techniques used to relate these values to antibacterial activity. A simple example of a QSAR descriptor is the total charge of a peptide. A large number of QSAR descriptors is available for small compounds in the literature and from commercial software products that may be considered. A smaller subset is used in QSAR studies of antibacterial peptides and may be separated into two categories descriptors based on empirical values and calculated descriptors. An example of an empirical value is HPLC retention time, which is a surrogate measure of solubility or hydrophilicity/hydrophobicity. An example of a calculated descriptor is total peptide charge at pH 7. 

A QSAR seeks to relate quantitative properties (descriptors) of a compound with other properties such as drug-like activity or toxicity. The essential assumption of QSAR is that quantities that can be conveniently measured or calculated for a compound can be used to accurately predict another property of interest (e.g., antibacterial activity) in a nontrivial way. QSAR has become an integral part of screening programs in pharmaceutical drug-discovery pipelines of small compounds and more recently in toxicological studies (69). However, the use of QSAR modeling applied to the search for antimicrobial peptides is relatively recent. Advances in this area are reviewed in brief here. 

GR 159897 is an indolylpiperidine, a TACHYKININ RECEPTOR ANTAGONIST selective for the NK -receptor subtype. It shows ANXIOLYTIC properties in animal models, gramicidin S [inn] is a (cyclic peptide) antibiotic. Active as an antibacterial and used clinically topically against Gram-positive bacteria. 

This model of the active site of transpeptidase has been used for the "rational" design of a novel antibacterial agent. A transition-state analog of the natural substrates inhibits bacterial peptide synthesis iji vitro.66... 

Gramicidin-S, cyclo[(Orn-Leu-D-Phe-Pro-Val)2], is a C2-symmetric, antibacterial, cyclic decapeptide. Structural studies have shown that the peptide conformation consists of two type IP p-turns with a connecting p-sheet. Based on molecular modeling studies and the results from earlier experimental studies of cyclic octapeptides, Ripka et al. at DuPont Merck Pharmaceuticals believed that the four amino acids that make up one of the p-turns could be replaced by a benzodiazepine (BZD) moiety. These authors designed the gramicidin-S analogue cyclo(Lys-Leu-D-Phe-Pro-Val-Lys-BZD) (95) based on... 

Tipper and Strominger (1965), by comparing molecular models of penicillin and D-alanyl-D-alanine claimed that the former could effectively function as a metabolite analogue of the latter. Thus the N to N" distances in these molecules, shown as projections of molecular models in (13.7) and (13.8), are identical, namely 3.3 A. Also the N" to C distances are similar in both models, namely 2.5 A. From N to C is 5.4 A in the penicillins and 5.7 A in alanyl-alanine, distances which are not identical but still quite similar. The D-con-figuration of the penicillin is maintained by the sulfur atom in conjunction with the carbon atom that is common to both rings. [Epimerization at the 6-position, see (13.4), causes loss of all antibacterial activity.] The most reactive bond in the penicillin molecule (the j8-lactam bond) corresponds in position to the peptide bond joining the two D-alanine residues. However, there are discrepancies the... 

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