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At least 37 records · Page 2Linked to original sources
PubMed2005

LEA3D: a computer-aided ligand design for structure-based drug design.

We present an improved version of the program LEA developed to design organic molecules. Rational drug design involves finding solutions to large combinatorial problems for which an exhaustive search is impractical. Genetic algorithms provide a tool for the investigation of such problems. New software, called LEA3D, is now able to conceive organic molecules by combining 3D fragments. Fragments were extracted from both biological compounds and known drugs. A fitness function guides the search process in optimizing the molecules toward an optimal value of the properties. The fitness function is build up by combining several independent property evaluations, including the score provided by the FlexX docking program. One application in de novo drug design is described. The example makes use of the structure of Mycobacterium tuberculosis thymidine monophosphate kinase to generate analogues of one of its natural substrates. Among 22 tested compounds, 17 show inhibitory activity in the micromolar range.

Algorithms↗
PubMed1992

Computer-aided drug design: getting the best results.

There are two major stages in the design of drug molecules: lead-molecule development and lead-molecule optimization. Whereas a variety of computational chemistry and molecular modeling (CC/MM) techniques are now routinely and successfully applied to the optimization stage of drug design, the generation of initial lead compounds has proven a more difficult problem for the CC/MM approach. Only recently has the design of lead molecules by this route become a subject of active research. This article looks at the factors which must be considered carefully when incorporating CC/MM methods into different aspects of drug-design strategies.

Computers↗
PubMed1997

Serendipity meets precision: the integration of structure-based drug design and combinatorial chemistry for efficient drug discovery.

Structure-based drug design uses three-dimensional visualization of drug candidates bound to a target receptor to direct structural modifications that increase potency. This widely used approach is limited by the difficulty of accurately predicting drug-binding affinities from three-dimensional structures. The integration of structure-based drug design with combinatorial chemistry can overcome this limitation by providing an empirical understanding of drug-binding energies. This integration allows compound synthesis and evaluation in parallel, and also helps assure that the compounds produced have properties consistent with good bioavailability and safety.

Biological Availability↗
PubMed2002

Application of hydrogen bonding calculations in property based drug design.

A drug can be characterized by "descriptors" that include size (volume) and H-bond acidity and H-bond basicity. These descriptors can be rapidly estimated from structure by a fragment scheme and used to predict physicochemical and transport properties of drug candidates (e.g. logP, solubility, gastrointestinal absorption, permeability and blood-brain distribution). The solvation equations can be interpreted to provide a qualitative chemical insight into biological partition and transport mechanisms. Applications to blood-brain partition and human intestinal absorption (HIA) are discussed.

Animals↗
PubMed1999

[Use of the pharmacophore concept in drug design].

The application of the pharmacophore concept to design new drugs is discussed. The focus is on the application of computer-assisted drug design methods (CADD) in the discovery of new leads.

Computer-Aided Design↗
PubMed2000

Toxicity of drug abuse--amphetamine designer drugs (ecstasy): mental effects and consequences of single dose use.

MDMA (3,4-methylendioxymethamphetamine) is the most commonly used substance within the 'ecstasy' group of drugs. MDMA interferes with serotonin and catecholamine transporters in the central nervous system to increase monoamine synaptic levels and thereby mediate the majority of its central nervous effects. These range from wanted effects like euphoria, central nervous stimulation, and feeling of closeness to mild hallucinations, impairment of cognition and co-ordination and further to serious reactions like agitation, disturbed and bizarre behaviour, and possibly psychosis. The full picture of the consequences of these transitory changes is not known. It has been assumed that the risk of being involved in fatalities and accidents during the state of MDMA influence is increased, but this possible risk increase has so far not been determined. Observations of the prevalence of MDMA involvement in cases of reckless driving and the MDMA blood concentrations measured indicate a risk increase comparable to that observed after use of amphetamines.

Accidents, Traffic↗
PubMed1996

A possible involvement of solvent-induced interactions in drug design.

We propose to study a new factor in designing new drugs. Most approaches to the drug design problem focus on the direct interactions between the drug and the corresponding target. We propose to study specific solvent-induced effects that can contribute to the binding Gibbs energy between the drug and its target. We estimate that these indirect effects will contribute significantly to the binding affinity and hopefully improve the clinical efficiency of the drugs.

Amino Acid Chloromethyl Ketones↗
PubMed2005

Metabolism of designer drugs of abuse.

Abuse of designer drugs is widespread among young people, especially in the so-called "dance club scene" or "rave scene", worldwide. Severe and even fatal poisonings have been attributed to the consumption of such drugs of abuse. However, in contrast to new medicaments, which are extensively studied in controlled clinical studies concerning metabolism, including cytochrome P450 isoenzyme differentiation, and further pharmacokinetics, designer drugs are consumed without any safety testing. This paper reviews the metabolism of new designer drugs of abuse that have emerged on the black market during the last years. Para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA) and 4-methylthioamphetamine (4-MTA), were taken into consideration as new "classical" amphetamine-derived designer drugs. Furthermore, N-benzylpiperazine (BZP), 1-(3, 4-methylenedioxybenzyl)piperazine (MDBP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP), 1-(3-chlorophenyl)piperazine (mCPP) and 1-(4-methoxyphenyl)piperazine (MeOPP) were taken into consideration as derivatives of the class of piperazine-derived designer drugs, as well as alpha-pyr-rolidinopropiophenone (PPP), 4'-methoxy-alpha-pyrrolidinopropiophenone (MOPPP), 3', 4'-methylenedioxy-alpha-pyrrolidino-propiophenone (MDPPP), 4'-methyl-alpha-pyrrolidinopropiophenone (MPPP), and 4'-methyl-alpha-pyrrolidinoexanophenone (MPHP) as derivatives of the class of alpha-pyrrolidinophenone-derived designer drugs. Papers describing identification of in vivo or in vitro human or animal metabolites and cytochrome P450 isoenzyme dependent metabolism have been considered and summarized.

Animals↗
PubMed1997

Retrometabolic approaches for drug design and targeting.

Retrometabolic drug design approaches incorporate targeting and metabolic considerations into the drug design process and represent a novel, systematic methodology for the design of safe, localized compounds. Two major design concepts aimed to increase the therapeutic index (the activity/toxicity ratio) of drugs were developed. Chemical delivery systems (CDS) are primarily used to allow targeting of the active biological molecules to specific target sites or organs based on predictable enzymatic activation. Brain-targeted delivery of different agents like estradiol or AZT was successfully achieved, and recent progresses include delivery of peptides using a complex strategy designated as molecular packaging. Sequential site- and stereospecific enzymatic activation of oxime/alkoxime precursors of beta-adrenergic antagonists allows their eye targeted delivery. Soft drug approaches are used to design new drugs by building in the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified subsequent to exerting its biological effects. Many examples are available to illustrate soft drug design, e.g., soft anticholinergics, soft b-blockers, soft antiinflammatory steroids. Special computer programs were developed that starting from a lead compound generate complete libraries of possible soft analogs and then help ranking these candidates based on molecular size/shape, electronic properties, predicted solubility/partition properties, and atomic charge distributions. Recent developments in the field are presented in a supplement to this issue.

Drug Delivery Systems↗
PubMed2000

Soft drug design: general principles and recent applications.

Soft drug design represents a new approach aimed to design safer drugs with an increased therapeutic index by integrating metabolism considerations into the drug design process. Soft drugs are new therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their therapeutic effect. Hence, they are obtained by building into the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified. In an attempt to systematize and summarize the related work done in a number of laboratories, including ours, the present review presents an overview of the general soft drug design principles and provides a variety of specific examples to illustrate the concepts. A number of already marketed drugs, such as esmolol, remifentanil, or loteprednol etabonate, resulted from the successful application of such design principles. Many other promising drug candidates are currently under investigation in a variety of fields including possible soft antimicrobials, anticholinergics, corticosteroids, beta-blockers, analgetics, ACE inhibitors, antiarrhythmics, and others. Whenever possible, pharmacokinetic and pharmacodynamic properties are briefly summarized and compared to those of other compounds used in the same field.

Drug Design↗
PubMed1997

Natural antisense RNA/target RNA interactions: possible models for antisense oligonucleotide drug design.

Current antisense oligonucleotides designed for drug therapy rely on Watson-Crick base pairing for the specificity of interactions between antisense and target molecules. However, thermodynamically stable duplexes containing non-Watson-Crick pairs have been formed with synthetic oligonucleotides. There are also numerous examples of non-canonical base pairs that participate in stable intra- and inter-molecular RNA/RNA pairing in prokaryotic and eukaryotic cells. Several natural antisense RNA/target RNA duplexes contain looped-out and bulged positions as well as non-canonical pairs as exemplified by formation of the Escherichia coli antisense micF RNA/ompF mRNA duplex. Secondary structures and the phylogenetic conservation of nucleotide sequences are well characterized in this system. Natural antisense/ target interactions may serve as models for determining possible and optimal antisense/target interactions in oligonucleotide drug design.

Bacterial Outer Membrane Proteins↗
PubMedDate not supplied

Alzheimer's drug design based upon an invertebrate toxin (anabaseine) which is a potent nicotinic receptor agonist.

Naturally occurring toxins can often serve as useful chemical tools for investigating signalling processes in nervous and other systems. Tetrodotoxin and alpha-bungarotoxin are prime examples of toxins which are widely used in neurobiological research. Some toxins may also become molecular models for designing new drugs. Usually drugs are small, non-peptide molecules, as these display better bioavailability, longer durations of action and are less likely to generate immune responses. The relatively large size and conformational flexibility of peptides and protein toxins makes them more challenging molecular models for rational drug design. This article considers a marine invertebrate toxin, anabaseine, and describes how manipulation of the structure of this alkaloid has provided a drug candidate which selectively stimulates mammalian brain alpha7 nicotinic receptors. Numerous anabaseine analogs were synthesized and subjected to a variety of pharmacological, behavioral and toxcicological tests. This led to the choice of GTS-21 (also known as 3-(2,4-dimethoxybenzylidene)-anabaseine or DMXBA), as a drug candidate for the treatment of Alzheimer's dementia. The chemical and pharmacological properties of GTS-21 are compared with those of the initial lead compound, anabaseine.

Alzheimer Disease↗
PubMed1995

New approaches and technologies in drug design and discovery.

Traditional and novel approaches to drug design and screening techniques and strategies are described, and the potential benefits of new technologies are discussed. Sophisticated new approaches and technologies in the discovery and design of new drugs are replacing the traditional methods. Rational or structure-based methods of drug design and discovery that integrate techniques of x-ray crystallography, computational chemistry, and nuclear magnetic resonance spectroscopy are becoming the predominant methods. New technologies and methods for drug screening may yield significant savings in time and money, as well as increased diversity and specificity of lead compounds. Intense research activity is now being focused on small-molecule structure-based drug design, in which drugs would mimic the complex molecular interactions of natural proteins. The new approaches and technologies hold promise for dramatic therapeutic advances, particularly in the areas of transcriptionally active drugs and gene therapy. Rapid advances in drug design and screening, brought about through new technologies, may yield significant therapeutic advances and cost-effective therapies.

Biological Products↗
PubMed2003

Feature selection and transduction for prediction of molecular bioactivity for drug design.

MOTIVATION: In drug discovery a key task is to identify characteristics that separate active (binding) compounds from inactive (non-binding) ones. An automated prediction system can help reduce resources necessary to carry out this task. RESULTS: Two methods for prediction of molecular bioactivity for drug design are introduced and shown to perform well in a data set previously studied as part of the KDD (Knowledge Discovery and Data Mining) Cup 2001. The data is characterized by very few positive examples, a very large number of features (describing three-dimensional properties of the molecules) and rather different distributions between training and test data. Two techniques are introduced specifically to tackle these problems: a feature selection method for unbalanced data and a classifier which adapts to the distribution of the the unlabeled test data (a so-called transductive method). We show both techniques improve identification performance and in conjunction provide an improvement over using only one of the techniques. Our results suggest the importance of taking into account the characteristics in this data which may also be relevant in other problems of a similar type.

Algorithms↗