Letters in Drug Design & Discovery - Volume 1, Issue 2, 2004

The synthesis and preliminary pharmacological profile of a new series of muscarinic antagonists are reported. Discrepancies between binding and functional studies have been found as the compounds of the series do not discriminate among muscarinic subtypes but do show functional selectivity in tissue assays. The most interesting compound 7 shows a good potency and selectivity for the muscarinic M3 receptors present in guinea pig ileum and may be a new lead for further studies.

The interaction of seventeen heteroarenium salts with the enzyme acetylcholinesterase was investigated using in vitro experiments. Rat brains were used as a source of the enzyme. All compounds involved in this study were found to be competitive acetylcholinesterase inhibitors. 10-methyl-acridinium iodide seems to be the most potent acetylcholinesterase inhibitor.

Alpha-lactalbumin (α-LA) and c-type lysozyme (cLZ) are two proteins structurally similar but largely different in their biochemical properties. Despite c-type lysozyme is widely distributed in nature from bacteria to human, α-lactalbumin is the only of mammalian products. These two proteins uniquely co-exist in mammalian milk but the significance of their distinct presence in milk is completely unknown. In this study, hen egg white lysozyme and bovine α-lactalbumin were investigated to elucidate the nature of their interaction and antibacterial synergy. A complex of cLZ and α-LA at one molar ratio exhibited greatly enhanced antibacterial activity against the Gram-positive Staphylococcus aureus and Gram-negative E. coli K-12. The catalytic activity of cLZ was unexpectedly increased with an increase of the molar ratio of α-LA to cLZ. Under physiological pH, α-LA was associated with cLZ in a dosedependent manner, as revealed by turbidity and intrinsic tryptophan fluorescence spectra measurements. Chemical cross-linking experiments accompanied with immunoblotting indicated that the complex existed mainly as cLZ-αLA heterodimer with cLZ homodimer. It is the first demonstration of distinct association between α-LA and cLZ with promising antimicrobial synergism. Our results strongly suggest the important role of cLZ and α-LA in the host defense system of the newborn against gastric microbial infections, and thus offer a great opportunity for the design of potential antimicrobial drug in the treatment of infectious diseases.

Bacillus anthracis, the etiologic agent of anthrax, is perceived as a potential biological warfare agent. In this review, recent advances made on infection process of B. anthracis are summarized and treatment strategies are discussed.

Three different 3D-QSAR methods namely CoMFA, CoMSIA and RSA were applied to a set of 38 angiotensin type 1 receptor (AT1) antagonists. The conformation and alignment of molecules used in each of the three QSAR methods were obtained by a novel method - Consensus Dynamics. To derive the best CoMFA model, various parameters such as partial charge formalism, grid spacing and the absolute orientation of the molecules in the grid were varied. The best CoMFA model had an r2 of 0.926 and a cross-validated correlation coefficient (q2) of 0.546, which improved with 'region focussing' to 0.710. The best CoMSIA model for the same set had an r2 of 0.969 and a q2 of 0.524. Likewise, the best RSA model with r2 of 0.893 and q2 of 0.639 resulted from optimization of various parameters such as atomic partial charges, surface fit and the manner of representation of electrostatics on the receptor surface. The models were thoroughly validated through trials using scrambled activities and bootstrapping. The predictive power of these models was evaluated on a test set that had almost 40% representation outside the training set. The three techniques were gainfully used to identify the structural features important for biological activity in these compounds.

This report describes the evaluation of a wide range of structurally diverse “privileged structures”, either amines or acids, linked via urea and amide connections, to the key dipeptide D-Trp-Lys-OMe. This led to the discovery of a collection of potent and structurally distinct SSTR2 ligands in both the amide and urea series. The 4- (benzimidazolone)-piperidine linked SSTR2 agonist (8) is highlighted.

We designed SDF-1α / CXCL12 (1) analogs to improve in vivo bioactivity. A linear analogue (2) consisting of AA1-14 of (1) joined by (Gly)4 to AA56-67 binds CXCR4, but with ∼100-fold less affinity. Cyclized analogs (3) and (4) were 2-3-fold more active. Substitution of the cysteines in analog (3) forming analog (5) prevented dimerization and increased plasma stability. Analogs (3) and (5) rapidly mobilized neutrophils and hematopoietic progenitor cells and synergized with G-CSF in normal mice.

Experimental studies have demonstrated that thalidomide, a drug developed as a sedative, has antitumoral properties. Its broad spectrum of actions besides its antiangiogenic potential, includes immunomodulatory properties, antiinflammatory actions and direct effect on tumor cells and their microenvironment. Multiple myeloma is so far the most responsive malignancy.

Subcutaneous vaccination of mice with chimerical polyomavirus-likeparticles consisting of a VP1-ovalbumin (OVA252-270) fusion protein induced immunodominant H-2Kb-restricted and OVA257-264-specific CD8 T cells in mice. Single immunisations with VP1-OVA252-270 capsoids failed to have beneficial effects on tumour protection, only double vaccinations in weekly intervals protected mice from lethal MO5 melanoma challenge.

The sympathetic nervous system (SNS) has a major role in homeostatic control of inflammatory and antigen specific immune reactions. This review summarizes the evidence that the SNS can enhance or suppress immune function, that SNS dysregulation is a critical component of the immune system dysregulation that underlies rheumatoid arthritis (RA) pathology and that the SNS may be targeted in RA to restore immune system homeostasis and reduce pathology. The potential for SNS targeted therapeutics comparable to the newly approved anti-TNF-α drugs is discussed.

To increase the peptide diversity of phage display libraries, we examined the incorporation of amino acid analogues into bacteriophage using auxotrophic E. coli strains. Fluorinated tryptophan analogues and norleucine were efficiently incorporated into phage particles. Phage display of unnatural amino acids may have wide applications in the drug discovery process.

Urocortin, expressed throughout the heart and vasculature, has potent effects on the cardiovascular system including vasodilation, increases in cardiac contractility and coronary blood flow, and protection of the myocardium against ischemia / reperfusion damage. This range of actions suggests urocortin has therapeutic potential in states of cardiac dysfunction and injury.

Preliminary experiments demonstrate that the results of dynamic combinatorial chemistry (DCC) processes can be deconvoluted using X-ray crystallography. The examples reported involve adduct formation between serine proteases, boric acid and a mixture of as many as eleven alcohols. Several DCC experiments are described and in each case X-ray crystallography provides a useful tool for product identification. These results demonstrate the assembly, selection and identification of products that form the basis of an experimental de novo drug design protocol.

Grid-based methods are widely used for evaluation of conformations in automated docking and other techniques of structure-based drug design. Traditional non-directional and directional methods for evaluating hydrogen bonds in these methods, however, yield improper interactions in cases with adjacent hydrogen bonds, such as those that mediate base pairing in nucleic acids. An improved method of calculating hydrogen bond potentials is reported here, which predicts the proper geometry for ligands that form multiple hydrogen bonds with receptors.