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Results for “Designer Drugs”

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At least 127 records · Page 7Linked to original sources
PubMed2005

The efficiency of multi-target drugs: the network approach might help drug design.

Despite considerable progress in genome- and proteome-based high-throughput screening methods and rational drug design, the number of successful single-target drugs did not increase appreciably during the past decade. Network models suggest that partial inhibition of a surprisingly small number of targets can be more efficient than the complete inhibition of a single target. This and the success stories of multi-target drugs and combinatorial therapies led us to suggest that systematic drug-design strategies should be directed against multiple targets. We propose that the final effect of partial, but multiple, drug actions might often surpass that of complete drug action at a single target. The future success of this novel drug-design paradigm will depend not only on a new generation of computer models to identify the correct multiple targets and their multi-fitting, low-affinity drug candidates but also on more-efficient in vivo testing.

Computational Biology↗
PubMed2003

Screening for and validated quantification of amphetamines and of amphetamine- and piperazine-derived designer drugs in human blood plasma by gas chromatography/mass spectrometry.

The classical stimulants amphetamine, methamphetamine, ethylamphetamine and the amphetamine-derived designer drugs MDA, MDMA ('ecstasy'), MDEA, BDB and MBDB have been widely abused for a relatively long time. In recent years, a number of newer designer drugs have entered the illicit drug market. 4-Methylthioamphetamine (MTA), p-methoxyamphetamine (PMA) and p-methoxymethamphetamine (PMMA) are also derived from amphetamine. Other designer drugs are derived from piperazine, such as benzylpiperazine (BZP), methylenedioxybenzylpiperazine (MDBP), trifluoromethylphenylpiperazine (TFMPP), m-chlorophenylpiperazine (mCPP) and p-methoxyphenylpiperazine (MeOPP). A number of severe or even fatal intoxications involving these newer substances, especially PMA, have been reported. This paper describes a method for screening for and simultaneous quantification of the above-mentioned compounds and the metabolites p-hydroxyamphetamine and p-hydroxymethamphetamine (pholedrine) in human blood plasma. The analytes were analyzed by gas chromatography/mass spectrometry in the selected-ion monitoring mode after mixed-mode solid-phase extraction (HCX) and derivatization with heptafluorobutyric anhydride. The method was fully validated according to international guidelines. It was linear from 5 to 1000 micro g l(-1) for all analytes. Data for accuracy and precision were within required limits with the exception of those for MDBP. The limit of quantification was 5 micro g l(-1) for all analytes. The applicability of the assay was proven by analysis of authentic plasma samples and of a certified reference sample. This procedure should also be suitable for confirmation of immunoassay results positive for amphetamines and/or designer drugs of the ecstasy type.

Amphetamines↗
PubMed2000

[Death caused by designer drugs].

OBJECTIVE: To draw pediatrician's attention to the risks of the use of designer drugs among adolescents and to review the problem. MATERIAL AND METHODS: We report the case of a 15-year-old girl admitted for seizures, who rapidly developed acute liver failure and died. Clinical and pathological details are reviewed. COMMENT: The use of designer drugs has increased considerably amongst Spanish adolescents and has been related to deaths in young adults with a variety of symptoms. Differential diagnosis should be made with the adverse effects of recreational drugs when clinical symptoms are confusing and in any unexplained deaths. Information on the effects of designer drugs should be disseminated among the population.

Acute Disease↗
PubMed2003

Virtual screening and rational drug design method using structure generation system based on 3D-QSAR and docking.

An efficient virtual and rational drug design method is presented. It combines virtual bioactive compound generation with 3D-QSAR model and docking. Using this method, it is possible to generate a lot of highly diverse molecules and find virtual active lead compounds. The method was validated by the study of a set of anti-tumor drugs. With the constraints of pharmacophore obtained by DISCO implemented in SYBYL 6.8, 97 virtual bioactive compounds were generated, and their anti-tumor activities were predicted by CoMFA. Eight structures with high activity were selected and screened by the 3D-QSAR model. The most active generated structure was further investigated by modifying its structure in order to increase the activity. A comparative docking study with telomeric receptor was carried out, and the results showed that the generated structures could form more stable complexes with receptor than the reference compound selected from experimental data. This investigation showed that the proposed method was a feasible way for rational drug design with high screening efficiency.

Colchicine↗
PubMed2002

Applications of NMR to structure-based drug design in structural genomics.

Structural genomics is poised to have a tremendous impact on traditional structure-based drug design programs. As a result, there is a growing need to obtain rapid structural information in a reliable form that is amenable to rational drug design. In this manner, NMR has been expanding and evolving its role in aiding the design process. A variety of NMR methodologies that cover a range of inherent resolution are described in the context of structure-based drug design in the era of structural genomics.

Chromatography, Gel↗
PubMed1993

Strategies for indirect computer-aided drug design.

This review is intended to describe some of the methods and procedures used for computer-aided drug design when the structure of the macromolecular target is unknown, as is the case for CNS active drugs. Strategies and methods used in computer-aided design of drugs in such instances must be "indirect," i.e., focusing on the characterization of the ligands themselves. This situation is different from one in which the three-dimensional structure of the macromolecular target for a drug is known, for example, for drugs that are enzyme inhibitors, allowing "direct" characterization of ligand-receptor interactions. Two qualitatively different "indirect" approaches are described here. One, called 2D-QSAR, is briefly reviewed. It is based on delineating regression relationships between a specified biological end point and properties of the compounds eliciting it. The other, based on pharmacophore development, constitutes the main part of this review. Several levels of pharmacophore development are described, which differ in the extent to which they encompass fundamental molecular properties that are determinants of receptor recognition and activation. The strengths and limitations of each procedure are discussed and illustrated by examples. Two methods for obtaining model receptor structures are then briefly described. Both rely on the prior success of the indirect methods in obtaining ligand properties that modulate receptor recognition and activation. These emerging capabilities have the potential to bridge the gap between indirect and direct methods of drug design, since, if successful, the design process can continue in a direct mode using explicit characterization of drug-receptor interactions. Strategies for hypothesis validation and use of hypothesis for drug design and discovery are also briefly reviewed. The final sections of this review describe specific computational tools such as molecular mechanics and quantum mechanical methods used to characterize and identify relevant molecular properties and indicate some areas for future development of computational chemistry methods that could increase its effectiveness in the design of novel drugs.

Computer Simulation↗
PubMed2002

Impact of mobility on structure-based drug design for the MMPs.

Structure-based approaches for drug design generally do not incorporate solvent effects and dynamic information to predict inhibitor-binding affinity because of practical limitations. The matrix metalloproteinases (MMPs) have previously been demonstrated to exhibit significant mobility in their active sites. This dynamic characteristic significantly complicates the drug design process based on static structures, which was clearly observed for a class of hydroxamic acids containing a butynyl moiety. Compound 1 was expected to be selective against MMP-1 based on predicted steric clashes between the butynyl P1' group and the S1' pocket, but the observation of complex inhibitor dynamics in the NMR structure of MMP-1:1 provides an explanation for the low nanomolar binding to MMP-1.

Binding Sites↗
PubMed1991

Pattern recognition methods in rational drug design.

Pattern recognition methods have much to offer the drug designer, particularly as the calculation and collation of data, both biological and physicochemical, becomes easier with the widespread use of computer databases, molecular modeling systems, and property prediction packages. Some of the techniques, however, suffer from difficulties in interpretation and the dangers of chance effects have received little attention. The wider use and understanding of these methods is expected to enhance their utility in drug design. Finally, it should be mentioned here that these methods are becoming applied increasingly in other areas of pharmaceutical research, e.g., the analysis of clinical data, and that new techniques for analysis continue to be developed and applied in this field.

Drug Design↗
PubMed2006

Progresses in the field of drug design to combat tropical protozoan parasitic diseases.

The progresses made in the field of drug design to combat tropical protozoan parasitic diseases, such as Chagas' disease, leishmaniasis, and sleeping sickness are discussed. This article is focused on different approaches based on unique aspects of parasites biochemistry and physiology, selecting the more promising molecular targets for drug design. In spite of the enormous amount of work on the above features, the chemotherapy for all of these diseases remains unsolved. It is based on old and fairly not specific drugs associated, in several cases, with long-term treatments and severe side effects. Drug resistance and different strains susceptibility are further drawbacks of the existing chemotherapy. In this review article, a thorough analysis of selected molecular targets, mainly those that are significantly different compared with the mammalian host or, even, are not present in mammals would be described in terms of their potencial usefulness for drug design. Therefore, this article covers rational approaches to the chemotherapeutic control of these parasitic infections, such as the progresses in the search for novel metabolic pathways in parasites that may be essential for parasites survival but with no counterpart in the host. Ergosterol biosynthesis is a very interesting example. There are many enzymes involved in this biosynthetic pathway such us squalene synthase, farnesylpyrophosphate synthase, and other enzymes that are able to deplete endogenous sterols will be treated in this article. The enzymes involved in trypanothione biosynthesis, glutathionyl spermidine synthetase and trypanothione synthetase do not have an equivalent in mammals, and therefore it can be predicted low toxicity for compounds that are able to produce highly selective inhibition. Trypanothione reductase (TR), glyceraldehyde-3-phosphate dehydrogenase, dihydrofolate reductase, prenyltransferases, ornithine decarboxylase, etc, will be thoroughly analyzed. The design of specific inhibitors of such metabolic activities as possible means of controlling the parasites without damaging the hosts will be presented. The recent advances in the biochemistry of pathogenic parasites including the discovery of novel organelles will be discussed.

Antiprotozoal Agents↗
PubMed1998

[Application of protein crystallography in drug design].

An overview of the application of protein crystallography in drug design is given in the paper. First a few basic principles of the systematic target based drug design discussed. Secondly are some problems encountered in the process of the protein crystallographic analysis are mentioned when it is applied to cases of pharmaceutical interest.

Crystallography, X-Ray↗
PubMed2003

Shape signatures: a new approach to computer-aided ligand- and receptor-based drug design.

A unifying principle of rational drug design is the use of either shape similarity or complementarity to identify compounds expected to be active against a given target. Shape similarity is the underlying foundation of ligand-based methods, which seek compounds with structure similar to known actives, while shape complementarity is the basis of most receptor-based design, where the goal is to identify compounds complementary in shape to a given receptor. These approaches can be extended to include molecular descriptors in addition to shape, such as lipophilicity or electrostatic potential. Here we introduce a new technique, which we call shape signatures, for describing the shape of ligand molecules and of receptor sites. The method uses a technique akin to ray-tracing to explore the volume enclosed by a ligand molecule, or the volume exterior to the active site of a protein. Probability distributions are derived from the ray-trace, and can be based solely on the geometry of the reflecting ray, or may include joint dependence on properties, such as the molecular electrostatic potential, computed over the surface. Our shape signatures are just these probability distributions, stored as histograms. They converge rapidly with the length of the ray-trace, are independent of molecular orientation, and can be compared quickly using simple metrics. Shape signatures can be used to test for both shape similarity between compounds and for shape complementarity between compounds and receptors and thus can be applied to problems in both ligand- and receptor-based molecular design. We present results for comparisons between small molecules of biological interest and the NCI Database using shape signatures under two different metrics. Our results show that the method can reliably extract compounds of shape (and polarity) similar to the query molecules. We also present initial results for a receptor-based strategy using shape signatures, with application to the design of new inhibitors predicted to be active against HIV protease.

Binding Sites↗
PubMed2002

Protein flexibility and computer-aided drug design.

Although computational techniques are increasingly being used in computer-aided drug design, the effects due to protein flexibility are still ignored in many applications. This review revisits rigorous statistical mechanical methods for predicting binding affinity, discusses some recent developments for improving their speed and reliability, and examines faster approximate models for facilitating virtual screening and lead optimization.

Computational Biology↗
PubMed1981

The theory of sets as a tool in systematic drug design.

A strategy of practical drug design is developed on the basis of the theory of sets. This strategy accounts for the fact that new drugs are required to optimally approach a certain activity profile rather than showing maximal intrinsic activity. In addition, modern structure selection techniques as well as qualitative and quantitative structure-activity relationships are incorporated in the strategy so as to optimally contribute to an economical use of experimental capacity.

Chemistry, Pharmaceutical↗
PubMed1999

Biochemical aspects of egg hatch in endo- and ectoparasites: potential for rational drug design.

Control of parasites through rational drug design requires a thorough understanding of the parasite's lifecycle encompassing the biochemical and physiological processes which contribute to normal parasite homeostasis. The hatching of parasite eggs for example, represents an important process in the development of a parasitic infection. Previous studies in helminths have indicated that secreted enzymes often facilitate successful endoparasite egg hatch. In contrast, there are relatively few examples demonstrating a role for secreted enzymes in the egg hatching process of insects. An analysis of this process in the ectoparasite Lucilia cuprina suggests a role for secreted enzymes in the hatching of sheep blowfly eggs. Characterisation of the proteases collected at the time of egg hatch indicates the presence of serine proteases. Further purification and characterisation of these proteases may enable the design of specific inhibitors to interfere with the egg hatch process and therefore provide a novel means of control.

Animals↗
PubMed2005

Application of 3D-QSAR techniques in anti-HIV-1 drug design--an overview.

Despite the availability of several classes of drugs against acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus type 1(HIV-1), this deadly disease showing very little sign of containment, especially in Sub-Saharan Africa and South-East Asia. More than 20 million people died since the first diagnosis of AIDS more than twenty years ago and almost 40 million people are currently living with HIV/AIDS. Structure-based drug design effort was immensely successful in identifying several drugs that are currently available for the treatment of HIV-1. Many applications have been reported on the use of quantitative structure-activity relationship (QSAR) studies to understand the drug-receptor interactions and help in the design of more effective analogs. Extensive application was also reported on the application of 3D-QSAR techniques, such as, Comparative Molecular Field Analysis (CoMFA), Comparative Molecular Similarity Analysis (CoMSIA), pharmacophore generation using Catalyst/HypoGen, free-energy binding analysis, GRID/GOLPE, HINT-based techniques, etc. in anti-HIV-1 drug discovery programs in academia and industry. We have attempted to put together a comprehensive overview on the 3D-QSAR applications in anti-HIV-1 drug design reported in the literature during the last decade.

Drug Design↗
PubMed2001

Industrial-scale, genomics-based drug design and discovery.

The demands on drug discovery organizations have increased dramatically in recent years, partly because of the need to identify novel targets that are both relevant to disease and chemically tractable. This is leading to an industrial approach to traditional biology and chemistry, inspired in part by the revolution in genomics. The purpose of this article is to highlight the flow of investigation from gene sequence of potential therapeutic targets, through mRNA and protein expression, to protein structure and drug design. To deal with this scale of activity, many commercial and public organizations have been established and some of the key players will be listed in this article.

Drug Design↗
PubMed1998

Structure-based drug design.

Most of the techniques used in structure-based drug design have experienced significant improvements in the past few years, resulting in a marked enhancement of the speed and the efficacy of this approach. At the same time, it was thought that the future of drug design lay in strategies involving solely combinatorial chemistry. It is becoming evident, however, that the development of future drugs will use a combination of methods that will contain a major component of structure-based design.

Databases, Factual↗