PubMed Health⌕ Search

Biomedical subjects

Donald F Weaver

Publications and source records attributed to Donald F Weaver.

At least 19 recordsLinked to original sources
PubMed2006

Molecular modelling of the GABAA ion channel protein.

The GABAA ion channel protein is central to the mechanism of action of general anaesthetics and thus to the phenomenon of human consciousness. A molecular model of the alpha1beta2gamma2 gamma-aminobutyric acid type-A (GABAA) ligand-gated ion channel protein has been constructed. The cryo-electron microscopy structure of the nicotinic acetylcholine receptor (nAChR) from Torpedo marmorata and the X-ray crystal structure of the acetylcholine binding protein (AChBP) from Lymnaea stagnalis were used as starting templates for comparative modelling. Features of the modelling approach used in the development of this GABAA model include: (1) multiple sequence alignment of members of the Cys-loop superfamily; (2) the design and implementation of a quasi-ab initio loop modelling algorithm; (3) expansion of the transmembrane domain (TMD) ion pore to model the open-state of the GABAA channel; (4) hydrophobicity analysis of the TMD to refine the structure in regions involved in general anaesthetic binding. The final model of the alpha1beta2gamma2 GABAA protein agrees with available experimental data concerning general anaesthetics.

Amino Acid Sequence↗
PubMed2006

Evaluating spousal abuse as a potential risk factor for Alzheimer's disease: rationale, needs and challenges.

BACKGROUND: Repetitive head trauma is an identified risk factor for Alzheimer's disease (AD). The violence in wife assault is repetitive and targets the head. This association provides a rationale for studying the relationship between spousal abuse and AD. DESIGN: To preliminarily evaluate the possibility of an increased susceptibility for AD in women subjected to spousal abuse and to identify challenges associated with such a study, we performed a pilot case-control study involving women with AD and compared the incidence of spousal abuse against two control groups. Forty consecutive women with AD referred to a Memory Disorders Clinic were enrolled. Individuals were evaluated at three visits (0, 3, 9 months) and were followed for an additional 12 months to ensure that no other diagnosis emerged. Two control groups were likewise assessed. RESULTS: 17.5% (7/40) of the women (average age 71 years) with AD reported spousal abuse with head trauma. In control group 1, 5.0% (2/40) and in control group 2, 7.5% (3/40) of the women reported spousal abuse with head trauma. CONCLUSIONS: The development of AD may be a potential long-term consequence of wife assault. Our study suggests spousal abuse as a possible risk factor for AD, and supports the need for larger studies. However, there are practical challenges associated with the successful execution of such a study.

Aged↗
PubMed2005

Morphine, gabapentin, or their combination for neuropathic pain.

BACKGROUND: The available drugs to treat neuropathic pain have incomplete efficacy and dose-limiting adverse effects. We compared the efficacy of a combination of gabapentin and morphine with that of each as a single agent in patients with painful diabetic neuropathy or postherpetic neuralgia. METHODS: In this randomized, double-blind, active placebo-controlled, four-period crossover trial, patients received daily active placebo (lorazepam), sustained-release morphine, gabapentin, and a combination of gabapentin and morphine--each given orally for five weeks. The primary outcome measure was mean daily pain intensity in patients receiving a maximal tolerated dose; secondary outcomes included pain (rated according to the Short-Form McGill Pain Questionnaire), adverse effects, maximal tolerated doses, mood, and quality of life. RESULTS: Of 57 patients who underwent randomization (35 with diabetic neuropathy and 22 with postherpetic neuralgia), 41 completed the trial. Mean daily pain (on a scale from 0 to 10, with higher numbers indicating more severe pain) at a maximal tolerated dose of the study drug was as follows: 5.72 at baseline, 4.49 with placebo, 4.15 with gabapentin, 3.70 with morphine, and 3.06 with the gabapentin-morphine combination (P<0.05 for the combination vs. placebo, gabapentin, and morphine). Total scores on the Short-Form McGill Pain Questionnaire (on a scale from 0 to 45, with higher numbers indicating more severe pain) at a maximal tolerated dose were 14.4 with placebo, 10.7 with gabapentin, 10.7 with morphine, and 7.5 with the gabapentin-morphine combination (P<0.05 for the combination vs. placebo, gabapentin, and morphine). The maximal tolerated doses of morphine and gabapentin were lower (P<0.05) with the combination than for each drug as single agent. At the maximal tolerated dose, the gabapentin-morphine combination resulted in a higher frequency of constipation than gabapentin alone (P<0.05) and a higher frequency of dry mouth than morphine alone (P<0.05). CONCLUSIONS: Gabapentin and morphine combined achieved better analgesia at lower doses of each drug than either as a single agent, with constipation, sedation, and dry mouth as the most frequent adverse effects.

Adult↗
PubMed2005

The "promiscuous drug concept" with applications to Alzheimer's disease.

Arguably, Alzheimer's disease (AD) is a multifactorial syndrome, rather than single disease, arising from a complex array of neurochemical factors. Numerous studies on the molecular pathogenesis of AD implicate a diversity of factors ranging from neurotoxic peptides (beta-amyloid) to inflammatory processes (interleukins), but all culminating in a common neuropathology. This diversity of molecular causation is an impediment to the design of effective therapies for AD. To address this design problem, we sought to identify a single, common motif (a "common receptor") shared by multiple structurally and functionally diverse proteins implicated in AD. This search revealed the presence of a common BBXB peptide motif and upon refinement, an AXBBXB motif; these regions can be exploited for the design of a "promiscuous drug" that exploits a "one-drug-multiple-receptors" therapeutic strategy for AD.

Alzheimer Disease↗
PubMed2005

A spontaneous recurrent seizure bioassay for anti-epileptogenic molecules.

Drug design in epilepsy is now tackling a new target--epileptogenesis. This is the process whereby a normal brain becomes susceptible to recurrent seizures. One of the stumbling blocks in the design and discovery of new chemical entities as antiepileptogenics is the implementation of an appropriate biological model. Current models, such as the maximal electroshock model, are models of seizures, not models of epileptogenesis. To develop such a model, we have extended and modified a chronic pilocarpine spontaneous recurrent seizure (SRS) model for the purposes of developing a bioassay with which to screen new compounds for putative antiepileptogenic bioactivity.

Animals↗
PubMed2004

Benzhydryl as an efficient selective nitrogen protecting group for uracils.

Regioselective N-substitution of the less active nitrogen within uracil analogues has been achieved following preliminary N-protection at the more active N-position with a benzhydryl protecting group. This protecting group is stable to concentrated HCl (aqueous) at reflux temperature, TFA at room temperature, and Pd-C-catalyzed normal pressure hydrogenation at room temperature; the benzhydryl group can be removed quantitatively and selectively with a 10% triflic acid solution in TFA at 0 degree C.

Journal Article↗
PubMed2004

A comparison of methods for modeling quantitative structure-activity relationships.

A large number of methods are available for modeling quantitative structure-activity relationships (QSAR). We examine the predictive accuracy of several methods applied to data sets of inhibitors for angiotensin converting enzyme, acetylcholinesterase, benzodiazepine receptor, cyclooxygenase-2, dihydrofolate reductase, glycogen phosphorylase b, thermolysin, and thrombin. Descriptors calculated with CoMFA, CoMSIA, EVA, HQSAR, and traditional 2D and 2.5D descriptors were used for developing models with partial least squares (PLS). In addition, the genetic function approximation algorithm, genetic PLS, and back-propagation neural networks were used for deriving models from 2.5D descriptors (i.e., 2D descriptors and 3D descriptors calculated from CORINA structures and Gasteiger-Marsili charges). Predictive accuracy was assessed using designed test sets. It was found that HQSAR generally performs as well as CoMFA and CoMSIA; other descriptor sets performed less well. When 2.5D descriptors were used, only neural network ensembles were found to be similarly or more predictive than PLS models. In addition, we show that many cross-validation procedures yield similar estimates of the interpolative accuracy of methods. However, the lack of correspondence between cross-validated and test set predictive accuracy for four sets underscores the benefit of using designed test sets.

Algorithms↗
PubMed2004

Molecular modeling of the von Willebrand factor A2 Domain and the effects of associated type 2A von Willebrand disease mutations.

A homology model for the A2 domain of von Willebrand factor (VWF) is presented. A large number of target-template alignments were combined into a consensus alignment and used for constructing the model from the structures of six template proteins. Molecular dynamics simulation was used to study the structural and dynamic effects of eight mutations introduced into the model, all associated with type 2A von Willebrand disease. It was found that the group I mutations G1505R, L1540P and S1506L cause significant deviations over multiple regions of the protein, coupled to significant thermal fluctuations for G1505R and L1540P. This suggests that protein instability may be responsible for their intracellular retention. The group II mutations R1597W, E1638K and G1505E caused single loop displacements near the physiologic VWF proteolysis site between Y1605-M1606. These modest structural changes may affect interactions between VWF and the ADAMTS13 protease. The group II mutations I1628T and L1503Q caused no significant structural change in the protein, suggesting that inclusion of the protease in this model is necessary for understanding their effect. [Figure: see text]. Homology model of the von Willebrand factor A2 domain

Amino Acid Sequence↗
PubMed2004

Pruned receptor surface models and pharmacophores for three-dimensional database searching.

A pharmacophore represents the 3D arrangement of chemical features that are shared by molecules exhibiting activity at a protein receptor. Pharmacophores are routinely used in 3D database searching for identifying potential lead compounds. The lack of shape constraints causes the query to identify compounds that could not fit into the active site. In the absence of structural information, a receptor surface model (RSM) can be used to represent the active site. The RSM consists of a surface that envelops a set of known actives after these have been aligned using their common features. When used for database searching, a RSM is overconstraining as it restricts access to regions that could be occupied by ligands, such as the solvent-protein interface or unexplored pockets. We describe a protocol for developing pruned RSMs using information gleaned from 3D quantitative structure-activity relationship (QSAR) models. We examined the performance of queries that consist of pharmacophores used alone or with pruned or unpruned RSMs by performing searches on six databases containing known actives distributed among inactives. The pruned RSMs yield an average selectivity 1.8 times greater than that for pharmacophore queries, compared to 1.6 times for unpruned RSMs. However, the pruned RSMs retrieve on average 73% of the actives identified using the pharmacophores, compared to 40% for the unpruned RSMs. As such, pruned RSMs represent a useful compromise between the high sensitivity of pharmacophores and the high selectivity of unpruned RSMs.

Amidines↗
PubMed2004

Density functional theory investigations on the chemical basis of the selectivity filter in the K+ channel protein.

The chemical-physical basis of loading and release of K(+) and Na(+) ions in and out of the selectivity filter of the K(+) channel has been investigated using the B3LYP method of density functional theory. We have shown that the difference between binding free energies of K(+) and Na(+) to the cavity end of the filter is smaller than the difference between the K(+) and Na(+) solvation free energies. Thus, the loading of K(+) ions into the cavity end of the selectivity filter from the solution phase is suggested to be selective prior to the subsequent conduction process. It is shown that the extracellular end of the filter is only optimal for K(+) ions, because K(+) ions prefer the coordination environment of eight carbonyl oxygens. Na(+) ions do not fit into the extracellular end of the filter, since they prefer the coordination environment of six carbonyl oxygens. Overall, the results suggest that the rigid C(4) symmetric selectivity filter is specifically designed for conduction of K(+) ions.

Cations, Monovalent↗
PubMed2004

"Organic" pseudoseizures as an unrecognized side-effect of anticonvulsant therapy.

Although pseudoseizures are a cause of drug toxicity (as escalating doses are used in an attempt to suppress seemingly intractable spells), in this brief report the exact converse is argued: namely, that a sub-group of pseudoseizures may arise as a reversible idiosyncratic toxic side-effect of GABAergic anticonvulsants. The term "organic pseudoseizures" is used to denote this group of medication related behavioural alterations.

Anticonvulsants↗
PubMed2004

Implementing a bioassay to screen molecules for antiepileptogenic activity: chronic pilocarpine versus subdudral haematoma models.

BACKGROUND: There is a need to discover novel chemical compounds that will inhibit the pathological process of epileptogenesis (i.e. agents that will prevent the long-term formation of an active seizure focus following a brain insult). The goal of this paper is to identify a bioassay of value in drug design when screening new chemical entities as putative antiepileptogenic agents. METHODS: We focused on two models: the pilocarpine chronic seizure model of spontaneous recurrent seizures (SRSs) and a chronic subdural haematoma model of SRSs. Both models were evaluated using more than 20 Sprague-Dawley rats for each model. RESULTS: In the pilocarpine-induced model of SRSs, 80% of animals went on to develop SRSs when the dose of pilocarpine was 380 mg/kg i.p. In 50 animals that developed SRSs, the average number of seizures per 15 days of observation was 3.8 seizures with a range of 2-23 seizures per 15-day period. The chronic subdural model was inefficient in producing SRSs. CONCLUSIONS: A pilocarpine-induced SRS model of epilepsy affords a reliable model of epileptogenesis suitable for evaluating new chemical entities as putative antiepileptogenics.

Animals↗
PubMed2004

A mathematical model for prediction of drug molecule diffusion across the blood-brain barrier.

BACKGROUND: Predicting the ability of drugs to enter the brain is a longstanding problem in neuropharmacology. The first step in creating a much-needed computational algorithm for predicting whether a drug will enter brain is to devise a rigorous mathematical model. METHODS: Employing two experimental measures of blood-brain barrier (BBB) penetrability (brain/plasma ratio and the brain-uptake index) and 14 theoretically derived biophysical predictors, a mathematical model was developed to quantitatively correlate molecular structure with ability to traverse the BBB. RESULTS: This mathematical model employs Stein's hydrogen bonding number and Randic's topological descriptors to correlate structure with ability to cross the BBB. The final model accurately predicts the ability of test molecules to cross the BBB. CONCLUSIONS: A mathematical method to predict blood-brain barrier penetrability of drug molecules has been successfully devised. As a result of bioinformatics, chemoinformatics and other informatics-based technologies, the number of small molecules being developed as potential therapeutics is increasing exponentially. A biophysically rigorous method to predict BBB penetrability will be a much-needed tool for the evaluation of these molecules.

Algorithms↗
PubMed2004

Three-dimensional quantitative structure-activity and structure-selectivity relationships of dihydrofolate reductase inhibitors.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling using comparative molecular similarity indices analysis (CoMSIA) was applied to a series of 406 structurally diverse dihydrofolate reductase (DHFR) inhibitors from Pneumocystis carinii (pc) and rat liver (rl). X-ray crystal structures of three inhibitors bound to pcDHFR were used for defining the alignment rule. For pcDHFR, a QSAR model containing 6 components was selected using leave-10%-out cross-validation (n= 240, q2 = 0.65), while a 4-component model was selected for rlDHFR (n= 237, q2 = 0.63); both include steric, electrostatic and hydrophobic contributions. The models were validated using a large test set, designed to maximise its diversity and to verify the predictive accuracy of models for extrapolation. The pcDHFR model has r2 = 0.60 and mean absolute error (MAE) = 0.57 for the test set after removing 4 outliers, and the rlDHFR model has r2 = 0.60 and MAE = 0.69 after removing 4 test set outliers. In addition, classification models predicting selectivity for pcDHFR over rlDHFR were developed using soft independent modelling by class analogy (SIMCA), with a selectivity ratio of 2 (IC50,rlDHFR/ IC50,pcDHFR) used for delimiting classes. A 5-component model including steric and electrostatic contributions has cross-validated and test set classification rates of 0.67 and 0.68 for selective inhibitors, and 0.85 and 0.72 for unselective inhibitors. The predictive accuracy of models, together with the identification of important contributions in QSAR and classification models, offer the possibility of designing potent selective inhibitors and estimating their activity prior to synthesis.

Animals↗
PubMed2003

Functionalized amido ketones: new anticonvulsant agents.

We have reported that functionalized amino acids (FAA) are potent anticonvulsants. Replacing the N-terminal amide group in FAA with phenethyl, styryl, and phenylethynyl units provided a series of functionalized amido ketones (FAK). We show that select FAK exhibit significant anticonvulsant activities thereby providing information about the structural requirements for FAA and FAK bioactivity.

Amides↗