Abstract Motivation: We analysed 148 human drug target proteins and 3573 non-drug targets to identify differences in their properties predict new potential targets. Results: Drug are rare organelles; they more likely be enzymes, particularly oxidoreductases, transferases or lyases not ligases; involved binding, signalling communication; secreted; have long lifetimes, shown by lack of PEST signals the presence N-glycosylation. This can summarized into eight key that desirable a target,...

The two hallmarks of Alzheimer's disease (AD) are the presence neurofibrillary tangles (NFT) made aggregates hyperphosphorylated tau protein and amyloid plaques composed amyloid-β (Aβ) peptides, primarily Aβ1–40 Aβ1–42. Targeting production, aggregation, toxicity Aβ with small molecule drugs or antibodies is an active area AD research due to general acceptance cascade hypothesis, but thus far all targeting have failed. From a review recent literature our own experience based on in vitro,...

We have determined the N- and C-capping preferences of all 20 amino acids by substituting residue X in peptides NH2-XAKAAAAKAAAAKAAGY-CONH2 Ac-YGAAKAAAAKAAAAKAX-CO2H. Helix contents were measured CD spectroscopy to obtain rank orders capping preferences. The data further analyzed our modified Lifson-Roig helix-coil theory, which includes parameters (n c), find free energies (-RT ln n -RT relative Ala. Results obtained for charged uncharged termini different states titratable side chains....

β-(25–35) is a synthetic derivative of β-amyloid, the peptide that believed to cause Alzheimer's disease. As it highly toxic and forms fibrillar aggregates typical suitable as model for testing inhibitors aggregation toxicity. We demonstrate thatN-methylated derivatives β-(25–35), which in isolation are soluble non-toxic, can prevent inhibit resulting toxicity wild type peptide.N-Methylation block hydrogen bonding on outer edge assembling amyloid. The peptides assayed by Congo red thioflavin...

Helix content of peptides with various uncharged nonaromatic amino acids at either the N-terminal or C-terminal position has been determined. The choice acid a major effect on helix stability: asparagine is best, glycine very good, and glutamine worst helix-stabilizing this position. rank order stabilization parallels frequencies these boundary (N-cap) helices in proteins found by Richardson [Richardson, J. S. & Richardson, D. C. (1988) Science 240, 1648-1652], peptide composed...

The key pathogenic event in the onset of Alzheimer's disease (AD) is believed to be aggregation β-amyloid (Aβ) peptide into toxic oligomers. Molecules that interfere with this process may therefore act as therapeutic agents for treatment AD. N-Methylated peptides (meptides) are a general class inhibitors by binding one face aggregating but unable hydrogen bond on other face, because N-methyl group replacing backbone NH group. Here, we optimize structure meptide Aβ aggregation, starting KLVFF...

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTToward the semiquantitative estimation of binding constants. Guides for peptide-peptide in aqueous solutionDudley H. Williams, Jonathan P. L. Cox, Andrew J. Doig, Mark Gardner, Ute Gerhard, Perry T. Kaye, Allick R. Lal, Ian A. Nicholls, Colin Salter, and Robert C. MitchellCite this: Am. Chem. Soc. 1991, 113, 18, 7020–7030Publication Date (Print):August 1, 1991Publication History Published online1 May 2002Published inissue 1 August...

Accurate identification of drug targets is a crucial part any development program. We mined the human proteome to discover properties proteins that may be important in determining their suitability for pharmaceutical modulation. Data was gathered concerning each protein’s sequence, post-translational modifications, secondary structure, germline variants, expression profile and target status. The data then analysed determine features which non-target had significantly different values. This...

Alzheimer's disease (AD) is characterized by the presence of β-amyloid plaques (Aβ) and neurofibrillary tangles (NFTs) in brain. The prevalence increasing expected to reach 141 million cases 2050. Despite risk factors associated with disease, there no known causative agent for AD. Clinical trials many drugs have failed over years, therapeutic has been approved There evidence that pathogens are found brains AD patients controls, such as human herpes simplex virus-1 (HSV-1). Given lack a...

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDetermination of Free Energies N-Capping in .alpha.-Helixes by Modification the Lifson-Roig Helix-Coil Theory To Include N- and C-CappingAndrew J. Doig, Avijit Chakrabartty, Tod M. Klingler, Robert L. BaldwinCite this: Biochemistry 1994, 33, 11, 3396–3403Publication Date (Print):March 22, 1994Publication History Published online1 May 2002Published inissue 22 March 1994https://doi.org/10.1021/bi00177a033RIGHTS & PERMISSIONSArticle...

It has long been believed that nucleation of the α-helix is a very fast reaction, occurring in around 10 −7 s. We show here helix nucleation, fact, takes place on millisecond time scale. The rate two polyalanine-based peptides and lysine glutamic acid homopolymers was measured directly by stopped-flow deep UV CD with synchrotron radiation as light source. Synchrotron gives far superior signal to noise than conventional instrument. 16-aa AK peptide folds first-order kinetics constant 15 s −1...

We have investigated the effect of placing phosphoserine at N-cap, N1, N2, N3, and interior position in alanine-based alpha-helical peptides. Helix contents each peptide were measured by CD spectroscopy titrations performed to determine pK(a) values. Data analyzed with modified Lifson-Roig theory helix-coil parameters (n, n(1), n(2), n(3), w) free energy changes for helical position. Results are given a -1 -2 charge state. show that stabilizes N-terminal positions as much 2.3 kcal.mol(-1),...

Abstract We have surveyed 393 N‐termini of α‐helices and 156 3 10 ‐helices in 85 high resolution, non‐homologous protein crystal structures for N‐cap side‐chain rotamer preferences, hydrogen bonding patterns, solvent accessibilities. find very strong preferences that are unique to sites. The following rules generally observed N‐capping α‐helices: Thr Ser side chains adopt the gauche— rotamer, bond N3 NH Ψ restricted 164 ± 8°. Asp Asn either with = 172 10°, or trans both N2 groups 107 19°....

Many neurodegenerative diseases are associated with the aggregation of misfolded proteins into amyloid oligomers or fibrils that deposited as pathological lesions within areas brain. An attractive therapeutic strategy for preventing ameliorating formation is to identify agents inhibit onset propagation protein aggregation. Here we demonstrate how solid-state nuclear magnetic resonance (ssNMR) may be used key residues amyloidogenic sequences targeted host protein. For α-synuclein, major...