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Biomedical subjects

Paul A Keller

Publications and source records attributed to Paul A Keller.

15 recordsLinked to original sources
PubMed2006

A new methodology for the simulation of flexible protein-ligand interactions.

A methodology has been developed for the simulation of induced fit between a ligand and its target protein. It utilizes constrained molecular dynamics where atoms determined to be immobile from difference distance matrix studies are fixed. Application of this methodology to HIV-1 reverse transcriptase (RT) as the example target protein has demonstrated its robustness. Short simulation times are sufficient to achieve good refinement of docking poses resulting from exchange of structurally dissimilar inhibitors between crystal structures.

Alkynes↗
PubMed2006

Synthesis and in vitro binding of N,N-dialkyl-2-phenylindol-3-yl-glyoxylamides for the peripheral benzodiazepine binding sites.

A series of N,N-dialkyl-2-phenylindol-3-ylglyoxylamides bearing the halogens iodine and bromine were synthesised and their binding affinity for the peripheral benzodiazepine binding sites (PBBS) in rat kidney mitochondrial membranes was evaluated using [(3)H]PK11195. Central benzodiazepine receptor (CBR) affinities were also evaluated in rat cortices using [(3)H]flumazenil to determine their selectivity for PBBS over CBR. The tested compounds had PBBS binding affinities (IC(50)) ranging from 7.86 to 618 nM, with all compounds showing high selectivity over the CBR (CBR IC(50) > 5000 nM). Among the 12 compounds tested, those with a diethylamide group were the most potent. The highest affinity iodinated PBBS ligand, N,N-diethyl-[5-chloro-2-(4-iodophenyl)indol-3-yl]glyoxylamide, was radiolabelled with iodine-123. This high affinity and selective radioligand may be useful for imaging neurodegeneration, inflammation and tumours using single photon emission computed tomography.

Amides↗
PubMed2006

The role of the HPA axis in psychiatric disorders and CRF antagonists as potential treatments.

An overview of the links between the Hypothalamic-Pituitary-Adrenal (HPA) axis and psychiatric disorders is presented. The current treatments are outlined, indicating that they are insufficient to meet the needs of those that suffer from these affective disorders. Therefore, there is an urgent need for the generation of new therapeutics, in particular, against new targets. The association of the corticotrophin releasing factor (CRF) and the HPA axis indicates that CRF antagonists should be beneficial as potential therapeutics.

Amino Acid Sequence↗
PubMed2005

Structural reassignment of the mono- and bis-addition products from the addition reactions of N-(Diphenylmethylene)glycinate esters to [60]fullerene under Bingel conditions.

The addition of N-(diphenylmethylene)glycinate esters (Ph2C=NCH2CO2R) to [60]fullerene under Bingel conditions gives [60]fullerenyldihydropyrroles and not methano[60]fullerenyl iminoesters [C60C(CO2R)(N=CPh2)] as previously reported. Unequivocal evidence for the structure of C60C(CO2Et)(N=CPh2) was provided by INADEQUATE NMR studies on 13C enriched material. New mechanistic details are proposed to account for the formation of [60]fullerenyldihydropyrroles and their reductive ring-opening reactions.

Journal Article↗
PubMed2005

Atroposelective synthesis of axially chiral biaryl compounds.

A rotationally hindered and thus stereogenic biaryl axis is the structurally and stereochemically decisive element of a steadily growing number of natural products, chiral auxiliaries, and catalysts. Thus, it is not surprising that significant advances have been made in the asymmetric synthesis of axially chiral biaryl compounds over the past decade. In addition to the classic approach (direct stereoselective aryl-aryl coupling), innovative concepts have been developed in which the asymmetric information is introduced into a preformed, but achiral-that is, symmetric or configurationally labile-biaryl compound, or in which an aryl--C single bond is stereoselectively transformed into an axis. This Review classifies these strategies according to their underlying concepts and critically evaluates their scope and limitations with reference to selected model reactions and applications. Furthermore, the preconditions required for the existence of axial chirality in biaryl compounds are discussed.

Journal Article↗
PubMed2005

Combining structure-based drug design and pharmacophores.

Development towards integrated computer-aided drug design methodologies is presented by utilising crystal structure complexes to produce structure-based pharmacophores. These novel pharmacophores represent the ligand features that are involved in interactions with the target protein, as well as the space around the ligand occupied by the protein. The protein-ligand complexes can also yield information about all interactions that ligands could potentially form with the binding site, as well as about the size of the binding cavity. Together, these describe a 'superligand', which can also be viewed as a pharmacophore. Various types of novel pharmacophores are discussed and compared, using HIV-1 reverse transcriptase (RT) as the target protein, and their application in database searching is presented.

Binding Sites↗
PubMed2003

Synthesis, molecular modeling and biological activity of methyl and thiomethyl substituted pyrimidines as corticotropin releasing hormone type 1 antagonists.

Four small, targeted libraries of differentially substituted amino pyrimidines were synthesized in moderate to good yields. Excellent regiochemistry was observed for substitution at C2/C4 with selectivity > 50:1 noted. All analogues were screened for their ability to interact with CRH1 and CRH2 receptors. In all instances only poor agonistic and/or antagonistic behaviour was noted at CRH2. However, several compounds were potent and selective CRH1 antagonists, most notably 13a Ki = 39 nM. Additionally we have utilized these data and that recently reported by others to refine our original CRH1 pharmacophore (J Med. Chem., 1999, 42, 2351-2357).

Cell Line↗
PubMed2003

Anilinopyrimidines as novel antituberculosis agents.

A selection of novel anilinopyrimidine analogues have been found to have micromolar activity against Mycobacterium tuberculosis. This could potentially generate new lead compounds in the fight against multi-drug resistant tuberculosis.

Animals↗
PubMed2003

Novel pharmacophore-based methods reveal gossypol as a reverse transcriptase inhibitor.

In a program to identify new structural entities for the inhibition of the HIV-1 reverse transcriptase (RT) enzyme via database searching, a series of RT pharmacophores were developed. By utilising a novel filtering technique, the National Cancer Institute database of compounds was scanned producing 15 compounds to be screened for activity. A notable inclusion was a series of gossypol derivatives. The testing of a series of compounds revealed the parent compound gossypol to be an HIV-1 reverse transcriptase inhibitor. These results suggest that at least a part of its anti-HIV activity is due to gossypol targeting the non-nucleoside inhibitor binding pocket of RT.

Databases, Factual↗
PubMed2002

Synthesis and characterization of mono- and bis-methano[60]fullerenyl amino acid derivatives and their reductive ring-opening retro-bingel reactions.

The addition of N-(diphenylmethylene)glycinate esters (Ph2C=NCH2CO2R) 3-6 to [60]fullerene under Bingel conditions gives, respectively, the methano[60]fullerenyl iminoesters 7-10. Upon treatment of 7-9 with sodium cyanoborohydride, in the presence of a protic or a Lewis acid, a novel reductive ring-opening reaction occurred to give the corresponding 1,2-dihydro[60]fullerenyl glycine derivatives 11-13. Using tethered bis-N-(diphenylmethylene)glycinate esters 33 and 34derived from m- and p-benzenedimethanol scaffolds, the corresponding bis-methano[60]fullerenyl iminoesters 35-38 were synthesized under double Bingel reaction conditions. The m-benzenedimethanol derivative 33 gave the trans-4 (35) and cis-3 (36) regioisomeric bisadducts in a ratio of 80:20. The analogous para-tethered derivative 34 afforded the trans-3 (37) and trans-4 (38) regioisomers in a 80:20 ratio. The regiochemistry of the major bisadducts 35 and 37 (via the trans-esterified 39) were unequivocally determined using 2D INADEQUATE and C-C TOCSY NMR experiments. The regiochemistry of these bis-additions were unexpected on the basis of literature precedents. These results unequivocally show that the regiochemistry of tethered bis-additions is not solely dependent on the nature of the tether. A mixture of the trans-4 and cis-3 nonsymmetrical bisadducts 45 and 46 was obtained from the double-Bingel cyclopropanation of a bis-N-(diphenylmethylene)glycinate tether based on a 1,3-naphthyldimethanol scaffold. The regiochemistry of these compounds (45 and 46) was identified by correlation with the diethyl esters 40 and 47, prepared by trans-esterification of 35/45 and 36/46, respectively. The INADEQUATE and molecular modeling experiments allowed topological mapping of the fullerene surfaces of the bis-methano[60]fullerenes 38 and 42. Reductive ring-opening reactions on the tethered bis-methano[60]fullerenes 35-37, 45, and 46 gave none of the expected bis-fullerenylglycinates rather the reductive ring-opening-retro-Bingel products, the 1,2-dihydro[60]fullerenylglycinates 48, 49, 52, and 53. These compounds resulted from the reductive ring-opening of one methanoimino ester moiety and a retro-Bingel reaction of the other. Under analogous reductive ring-opening-retro-Bingel conditions, the nontethered bis-methano[60]fullerene 40 afforded the 1,2-dihydro[60]fullerenylglycinate 12. Thus, it was concluded that the tether was not the driving force for the reductive elimination of one of the methano groups.

Amino Acids↗
PubMed2002

New anti-malarial compounds from database searching.

In a serendipitous result, pharmacophores generated for the database searching for new non-nucleoside inhibitors of the HIV-1 reverse transcriptase enzyme unearthed 12 new lead compounds which were active against the Plasmodium falciparum strain of malaria.

Animals↗
PubMed2002

Mining the Chemical Abstracts database with pharmacophore-based queries.

A method is described to convert 3D patterns of pharmacophoric groups into 2D queries for molecular substructure searches of the Chemical Abstracts database with SciFinder Scholar. The results of such searches and the options for refinement of the hit lists are presented using a rigid tetrahydroisoquinoline-carbazole (IQC) hybrid molecule fitted onto previously developed pharmacophores for subtype-selective alpha1-adrenergic receptor antagonists as an example. The compounds retrieved were further analysed by limiting their physical properties to 'drug-like' ranges and by enumerating the ring skeletons they contain. Selected ring skeletons were evaluated by fitting them on to the original pharmacophores. Several structurally novel rigid ring skeletons were found with this new database mining technique which are potentially useful as leads in the design of alpha1B selective adrenergic receptor antagonists.

Adrenergic alpha-1 Receptor Antagonists↗