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Biomedical subjects

Renate Griffith

Publications and source records attributed to Renate Griffith.

11 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

Selective pharmacophore design for alpha1-adrenoceptor subtypes.

Alpha1-adrenoceptors are G-protein coupled receptors found in a variety of vascular tissues and responsible for vasoconstriction. Selectivity for each of the three subtypes is an important consideration in drug design in order to minimise the possibility of side effects. Using Catalyst we developed ligand-based pharmacophores from alpha(1a,b,d)-selective antagonists available in the literature using three separate training sets. Four-feature pharmacophores were developed for the alpha(1a) and alpha(1b) subtype-selective antagonists and a five-feature pharmacophore was developed for the alpha(1d) subtype-selective antagonists. The alpha(1a) pharmacophore represents both class I and II compounds with good predictivity for other compounds outside the training set as well. The alpha(1b) pharmacophore best predicts the activity of prazosin analogues as these make up the majority of alpha(1b)-selective antagonists. Unexpectedly, no positive ionisable feature was incorporated in the alpha(1b) pharmacophore. The alpha(1d) pharmacophore was based primarily on one structural class of compounds, but has good predictivity for a heterogeneous test set. Preliminary docking studies using AutoDock and optimised alpha1-adrenoceptor homology models, conducted with the antagonists prazosin (32) and 66, showed good agreement with the findings from the pharmacophores.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2005

Homology modelling of RNA polymerase and associated transcription factors from Bacillus subtilis.

RNA polymerase (RNAP) is the central enzyme of transcription and requires interaction with transcription factors in vivo for correct processivity. Both the transcription initiation complex and the ternary elongation complex are stabilised by and require protein-protein interactions between the various components involved. These interactions may form the basis for rational design of small peptide mimics of one or more proteins involved in order to inhibit protein-protein interactions and thus transcription. Here, we present homology models of the model Gram positive organism Bacillus subtilis RNA polymerase in the core and holoenzyme forms. Interactions between RNA polymerase and the transcription factor sigmaA were investigated in order to design peptide mimics of the major interactions.

Bacillus subtilis↗
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↗
PubMed2004

Synthesis and biological evaluation of bicyclic and tricyclic substituted nortropane derivatives: discovery of a novel selective alpha1D-adrenergic receptor ligand.

A range of 3,6,6-trisubstituted nortropane derivatives based upon 6beta-phenyltropane-3beta,6 alpha-diol have been synthesised from 6beta-hydroxytropinone, including some novel related tricyclic hemi-ketal and tricyclic ketal compounds. Derivatives were assessed for pharmacological affinity and selectivity at alpha(1)-adrenergic receptors, and 6beta-phenyl-8-azabicyclo[3.2.1]octan-3-spiro-2'-(1',3'-dioxolane)-6-ol, a novel lead compound selective for the alpha(1D)-adrenergic receptor, is reported.

Animals↗
PubMed2004

Molecular basis of the constitutive activity and STI571 resistance of Asp816Val mutant KIT receptor tyrosine kinase.

The receptor tyrosine kinase, KIT, displays activating mutations in the kinase domain, which are associated with various cancers. We have used homology modelling based on the crystal structures of the insulin receptor kinase in active and inactive conformations to predict the corresponding structures of the KIT kinase domain. We have prepared four KIT models, one each for the active and inactive conformations of the wild-type and of the Asp816Val mutant proteins. We have also placed ATP into the active conformations and the inhibitor, STI571, into the inactive conformations. All models have been fully energy minimised. The molecular modelling studies described here explain (i) why Asp816Val KIT is constitutively active, (ii) why the nature of the substituting amino acid at residue 816 is relatively unimportant, and (iii) why the Asp816Val substitution confers resistance to the KIT-inhibitory drug STI571. The models will be valuable for predicting other kinase inhibitory drugs that may be active on wild-type and mutant forms of KIT. During the course of this work, a crystal structure of the active conformation of the KIT kinase domain has been published. Our model of the active conformation of the Asp816Val mutant is strikingly similar to this crystal structure, whereas our model of the active conformation of the wild-type kinase domain of KIT differs from the crystal structure in some respects. The reasons for this apparent discrepancy are discussed.

Amino Acid Sequence↗
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↗
PubMed2003

Comparative pharmacophore development for inhibitors of human and rat 5-alpha-reductase.

There are a number of diseases where the 5-alpha-reductase (5AR) enzyme is of therapeutic interest as a drug target. Currently the crystal structure for 5-alpha-reductase is unavailable, thus ligand-based pharmacophore techniques are beneficial in the drug development process. We have developed pharmacophores to aid inhibitor design for both human types I (preliminary) and II 5-alpha-reductase isozymes and also the rat type II isozyme. To our knowledge, these are the first published pharmacophores for inhibitors of the human type I and rat type II enzymes. A comparison between isozymes and the previously published human type II isozyme pharmacophore is also presented.

Animals↗
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↗