Biomedical subjects

Alan C Gibbs

Publications and source records attributed to Alan C Gibbs.

7 recordsLinked to original sources

PubMed2006

Identification of 2-acylaminothiophene-3-carboxamides as potent inhibitors of FLT3.

A series of 2-acylaminothiophene-3-carboxamides has been identified which exhibit potent inhibitory activity against the FLT3 tyrosine kinase. Compound 44 inhibits the isolated enzyme (IC50 = 0.027 microM) and blocks the proliferation of MV4-11 cells (IC50 = 0.41 microM). Structure-activity relationship studies within this series are described in the context of a proposed binding model within the ATP binding site of the enzyme.

Amides↗

PubMed2005

Comparison of automated docking programs as virtual screening tools.

The performance of several commercially available docking programs is compared in the context of virtual screening. Five different protein targets are used, each with several known ligands. The simulated screening deck comprised 1000 molecules from a cleansed version of the MDL drug data report and 49 known ligands. For many of the known ligands, crystal structures of the relevant protein-ligand complexes were available. We attempted to run experiments with each docking method that were as similar as possible. For a given docking method, hit rates were improved versus what would be expected for random selection for most protein targets. However, the ability to prioritize known ligands on the basis of docking poses that resemble known crystal structures is both method- and target-dependent.

Binding Sites↗

PubMed2005

Docking: successes and challenges.

The state of the art of various computational aspects of docking-based virtual screening of database of small molecules is presented. The review encompasses the different search algorithms and the scoring functions used in docking methods and their applications to protein and nucleic acid drug targets. Recent progress made in the development and application of methods to include target flexibility are summarized. The fundamental issues and challenges involved in comparing various docking methods are discussed. Limitations of current technologies as well as future prospects are presented.

Algorithms↗

PubMed2004

NMR solution structure of the precursor for carnobacteriocin B2, an antimicrobial peptide from Carnobacterium piscicola.

Type IIa bacteriocins, which are isolated from lactic acid bacteria that are useful for food preservation, are potent antimicrobial peptides with considerable potential as therapeutic agents for gastrointestinal infections in mammals. They are ribosomally synthesized as precursors with an N-terminal leader, typically 18-24 amino acid residues in length, which is cleaved during export from the producing cell. We have chemically synthesized the full precursor of carnobacteriocin B2, precarnobacteriocin (preCbnB2), which has a C-terminal amide rather than a carboxyl, and also produced preCbnB2(1-64), which is missing two amino acid residues at the C-terminus (Arg65 and Pro66), via expression in Escherichia coli as a maltose-binding protein fusion that is then cut with Factor Xa. PreCbnB2(1-64) is readily labeled with (15)N and (13)C for NMR studies using the latter approach. Multidimensional NMR analysis of preCbnB2(1-64) shows that, like the parent bacteriocin, it exists as a random coil in water but assumes a defined conformation in water/trifluoroethanol mixtures. In 70 : 30 trifluoroethanol/water, the 3D structure of the preCbnB2 section corresponding to the mature bacteriocin is essentially the same as reported previously by us for carnobacteriocin B2 (CbnB2). This structure maintains the highly conserved alpha-helix corresponding to residues 20-38 of CbnB2 that is believed to be responsible for interaction with a target receptor in sensitive cells, including Listeria monocytogenes. PreCbnB2 also has a second alpha-helix from residues 3-13 (i.e. -15 to -5 relative to CbnB2) in the leader section of the peptide. This helix appears to be conserved in related type IIa bacteriocin precursors based on sequence analysis. It is likely to be a key recognition element for export and processing, and is probably responsible for the considerably reduced antimicrobial activity of preCbnB2. The latter effect may assist the producing cell in avoiding the toxic effects of the bacteriocin. This is the first 3D structure determined for a prebacteriocin from lactic acid bacteria.

Amino Acid Sequence↗

PubMed2003

Nanosecond temperature jump relaxation dynamics of cyclic beta-hairpin peptides.

The thermal unfolding of a series of 6-, 10-, and 14-mer cyclic beta-hairpin peptides was studied to gain insight into the mechanism of formation of this important secondary structure. The thermodynamics of the transition were characterized using temperature dependent Fourier transform infrared spectroscopy. Thermodynamic data were analyzed using a two-state model which indicates increasing cooperativity along the series. The relaxation kinetics of the peptides in response to a laser induced temperature jump were probed using time-resolved infrared spectroscopy. Single exponential relaxation kinetics were observed and fit with a two-state model. The folding rate determined for these cyclic peptides is accelerated by some two orders of magnitude over the rate of a linear peptide that forms a beta-hairpin. This observation supports the argument that the rate limiting step in the linear system is either stabilization of compact collapsed structures or rearrangement of collapsed structures over a barrier to achieve the native interstrand registry. Small activation energies for folding of these peptides obtained from an Arrhenius analysis of the rates imply a primarily entropic barrier, hence an organized transition state having specific stabilizing interactions.

Kinetics↗

PubMed2002

Probing the structural determinants of type II' beta-turn formation in peptides and proteins.

The structural determinants of type II' beta-turns were probed through a comprehensive CD, NMR, and molecular dynamics analysis of 10 specially designed beta-hairpin peptides. The peptide model used in this study is a synthetic, water-soluble, 14-residue cyclic analogue of gramicidin S which contains two well-defined type II' beta-turns connected by a highly stable, amphipathic, antiparallel beta-sheet. A variety of coded and noncoded amino acids were systematically substituted in one of the two type II' turns to analyze the effects of backbone chirality, side-chain steric restriction, and side-chain/side-chain interactions. beta-Sheet content (as measured through a variety of experimental methods), molecular dynamics, and 3D structural analysis of the turn regions were used to assess the effects of each amino acid substitution on type II' beta-turn stabilization. Our results demonstrate that backbone heterochirality, which determines equatorial and axial side-chain orientation at the i+1 and i+2 residues of type II' turns, may account for up to 60% of type II' beta-turn stabilization. Steric restriction through side-chain N-alkylation appears to enhance type II' beta-turn propensity and may account for up to 20% of type II' beta-turn stabilization. Finally, aromatic/proline side-chain interactions appear to account for approximately 10% of type II' beta-turn stabilization. We believe this information could be particularly useful for the prediction of beta-turn propensity, the development of peptide-based drugs, and the de novo design of peptides, proteins, and peptidyl mimetics.

Circular Dichroism↗

PubMedDate not supplied

A cluster-based strategy for assessing the overlap between large chemical libraries and its application to a recent acquisition.

We report on the structural comparison of the corporate collections of Johnson & Johnson Pharmaceutical Research & Development (JNJPRD) and 3-Dimensional Pharmaceuticals (3DP), performed in the context of the recent acquisition of 3DP by JNJPRD. The main objective of the study was to assess the druglikeness of the 3DP library and the extent to which it enriched the chemical diversity of the JNJPRD corporate collection. The two databases, at the time of acquisition, collectively contained more than 1.1 million compounds with a clearly defined structural description. The analysis was based on a clustering approach and aimed at providing an intuitive quantitative estimate and visual representation of this enrichment. A novel hierarchical clustering algorithm called divisive k-means was employed in combination with Kelley's cluster-level selection method to partition the combined data set into clusters, and the diversity contribution of each library was evaluated as a function of the relative occupancy of these clusters. Typical 3DP chemotypes enriching the diversity of the JNJPRD collection were catalogued and visualized using a modified maximum common substructure algorithm. The joint collection of JNJPRD and 3DP compounds was also compared to other databases of known medicinally active or druglike compounds. The potential of the methodology for the analysis of very large chemical databases is discussed.

Algorithms↗