PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Drug Design”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources
PubMed2003

Strategy of computer-aided drug design.

Modern strategies of computer-aided drug design (CADD) are reviewed. The task of CADD in the pipeline of drug discovery is accelerating of finding the new lead compounds and their structure optimization for the following pharmacological tests. The main directions in CADD are based on the availability of the experimentally determined three-dimensional structure of the target macromolecule. If spatial structure is known the methods of structure-based drug design are used. In the opposite case the indirect methods of CADD based on the structures of known ligands (ligand-based drug design) are used. The interrelationship between the main directions of CADD is reviewed. The main CADD approaches of molecule de novo design and database mining are described. They include methods of molecular docking, de novo design, design of pharmacophore and quantity structure-activity relationship models. New ways and perspectives of CADD are discussed.

Computational Biology↗
PubMed1998

Designer drugs: the evolving science of drug discovery.

Drug discovery and design are fundamental to drug development. Until recently, most drugs were discovered through random screening or developed through molecular modification. New technologies are revolutionizing this phase of drug development. Rational drug design, using powerful computers and computational chemistry and employing X-ray crystallography, nuclear magnetic resonance spectroscopy, and three-dimensional quantitative structure activity relationship analysis, is creating highly specific, biologically active molecules by virtual reality modeling. Sophisticated screening technologies are eliminating all but the most active lead compounds. These new technologies promise more efficacious, safe, and cost-effective medications, while minimizing drug development time and maximizing profits.

Biotechnology↗
PubMed2004

Predicting molecular interactions in silico: I. A guide to pharmacophore identification and its applications to drug design.

A major goal in contemporary drug design is to develop new ligands with high affinity of binding toward a given protein receptor. Pharmacophore, which is the three-dimensional arrangement of essential features that enable a molecule to exert a particular biological effect, is a very useful model for achieving this goal. If the three dimensional structure of the receptor is known, pharmacophore is a complementary tool to standard techniques, such as docking. However, frequently the structure of the receptor protein is unknown and only a set of ligands together with their measured binding affinities towards the receptor is available. In such a case, a pharmacophore based strategy is one of the few applicable tools. Here we present a broad, yet concise guide to pharmacophore identification and review a sample of applications for drug design. In particular, we present the framework of the algorithms, classify their modules and point out their advantages and challenges.

Algorithms↗
PubMed1981

Application of the theory of sets to drug design. Development of a new cardiotonic drug AR-L 115 BS.

A new type of cardiotonic compounds is developed by applying a systematic drug design procedure based on the theory of sets. With the aid of clinical and pharmacological experience in the field of cardiotonic drugs and from biomolecular considerations a structural field (set) is selected which is likely to contain compounds which show the desired activity profile. By systematic exclusion of inappropriate parts of this structural field (subsets) the original set is reduced to a small structural area (residue set) the structures (elements) of which have a high potential of being new cardiotonic drugs with an activity profile superior to hitherto known compounds. In our case one of the elements, 2-[(2-methoxy-4-methylsulfinyl)phenyl]-1H-imidazo[4,5-b]pyridine (AR-L 115 BS), proved to fulfil all the requirements of the medicinal objective. The structure of AR-L 115 differs significantly from all other cardiotonic principles and therefore represents an entirely new type of positive inotropic agents.

Cardiotonic Agents↗
PubMed1994

Radiation chemistry applied to drug design.

Radiation chemistry can contribute to drug design by quantifying redox properties of drugs (useful parameters in quantitative structure-activity relationships), and where free radicals are suspected intermediates in drug action, radiation can be used to generate these putative species and help characterize relevant reactions. Steady radiolysis produces radicals at a readily-varied but quantified rate; pulse radiolysis with fast spectrophotometric and/or conductimetric detection enables the kinetic properties of radicals to be monitored directly. Using these methods, radical intermediates from drugs with specific cytotoxicity towards hypoxic cells have been shown to react rapidly with oxygen, a reaction probably responsible for the therapeutic differential. Radical oxidants from activated neutrophils include superoxide and hydroxyl radicals, and radiation-chemical methods have an important role to play in rational drug design to exploit such oxidative chemistry. Antioxidants can also be evaluated quantitatively by radiolysis methods; the conjugation reactions of thiyl radicals with thiolate and oxygen are now recognised to be major contributions of pulse radiolysis to thiol biochemistry.

Drug Design↗
PubMed1994

A shape-based machine learning tool for drug design.

Building predictive models for iterative drug design in the absence of a known target protein structure is an important challenge. We present a novel technique, Compass, that removes a major obstacle to accurate prediction by automatically selecting conformations and alignments of molecules without the benefit of a characterized active site. The technique combines explicit representation of molecular shape with neural network learning methods to produce highly predictive models, even across chemically distinct classes of molecules. We apply the method to predicting human perception of musk odor and show how the resulting models can provide graphical guidance for chemical modifications.

Algorithms↗
PubMed1987

Progress and prospects for optimum antiarrhythmic drug design.

Different class I drugs slow down to differing degrees the rate at which sodium channel availability, hence excitability, recovers after action potentials. Drugs that produce longer recovery half-times generally produce greater proarrhythmic side effects. Increased lipid solubility may improve a drug's "potency" for blocking channels yet with implications for adverse effects. Drug action may be potentiated in depolarized and acidotic tissue via modulation of the recovery process. A knowledge of molecular properties of antiarrhythmic drugs helps to define these modes of interaction with the sodium channels and, hence, will help in future drug design. Prospects for improving our understanding of ionic events involved in the repolarization phase of cardiac action potentials are also outlined. The development of successful strategies for controlling reentrant arrhythmias will probably require a thorough understanding of both class I and class III drug actions at the level of the membrane ion channel.

Animals↗
PubMed1998

[Structure-based drug design].

Structure-based drug design is not only a fundamental tool in the search of new drugs but also an area of intensive scientific research. The present contribution starts with a critical analysis of the potentiality of the structure based design and then reviews its methods. Protein crystallography, NMR, homology modelling and the use of antibodies are either referenced or briefly described as the methods which are able to provide us with the atomic structure of receptors. The search of lead molecules by data base mining and by generating structures with computers is discussed. Various methods and computer programs for calculating the interaction energy between receptors and ligands are reviewed. Several examples of successful structure base design are cited and some of them are briefly discussed.

Computer Simulation↗
PubMed2006

Structural e-bioinformatics and drug design.

Nowadays the in silico scenario for drug design is totally dependent on structural biology and structural bioinformatics. A myriad of free bioinformatics applications and services have been posted on the web. This mini-review mentions web sites that are useful in structure-based drug design. The information is given in a logical manner, following the drug design process i.e. characterization of a protein target, modelling the protein using sequence homology, optimization of the protein structure and finally docking of small ligands into the active site.

Amino Acid Sequence↗
PubMed1992

[Rejection of physico-chemical indices for pathological matrix in a quantitative drug design].

In a quantitative drug design, correlation of coefficient matrix of physico-chemical indices Xi is often pathological when these indices are highly correlated. The regression equation of biological activity Y about these indices Xi obtained in this case is not stable. In this paper, a method is given to obtain a stable regression equation: giving a critical valne alpha and finding out the indices among which correlation coefficient is not less than alpha. The following are the rules to reject some of them. If Xi and Xj is highly correlated (magnitude of rij greater than or equal to alpha, rij is the correlation coefficient of Xi and Xj), and magnitude of rin greater than magnitude of rjn (rin and rjn are correlation coefficients of Xi and Xj about Y, respectively), than the index Xj is rejected, otherwise, Xi is rejected. Stable equation can be obtained by stepwise regression with the remaining indices.

Drug Design↗
PubMed2001

Incorporating target heterogeneity in drug design.

Traditionally, structure-based drug design has been predicated on the idea of the lock-and-key hypothesis, i.e., the ideal drug should have a structure that complements the target site structurally and energetically. The implementation of this idea has lead to the development of drug molecules that are conformationally constrained and pre-shaped to the geometry of the selected target. The main drawback of this strategy is that conformationally constrained molecules cannot accommodate to variability in the target and, therefore, lose significant binding affinity even in the presence of small changes in the target site. There are three common situations that lead to binding site heterogeneity: (1) genetic diversity; (2) drug resistant mutations; and (3) binding site dynamics. The development of drugs that effectively deal with target heterogeneity requires the introduction of certain degree of flexibility. However, flexibility cannot be introduced indiscriminately because it would lead to a loss of binding affinity and specificity. Recently, structure-based thermodynamic strategies aimed at developing adaptative ligands that target heterogeneous sites have been proposed. In this article, these strategies are discussed within the context of the development of second generation HIV-1 protease inhibitors.

Binding Sites↗
PubMed1999

Metabolism-based anticancer drug design.

Many conventional anticancer drugs display relatively poor selectivity for neoplastic cells, in particular for solid tumors. Furthermore, expression or development of drug resistance, increased glutathione transferases as well as enhanced DNA repair decrease the efficacy of these drugs. Research efforts continue to overcome these problems by understanding these mechanisms and by developing more effective anticancer drugs. Cyclophosphamide is one of the most widely used alkylating anticancer agents. Because of its unique activation mechanism, numerous bioreversible prodrugs of phosphoramide mustard, the active species of cyclophosphamide, have been investigated in an attempt to improve the therapeutic index. Solid tumors are particularly resistant to radiation and chemotherapy. There has been considerable interest in designing drugs selective for hypoxic environments prevalent in solid tumors. Much of the work had been centered on nitroheterocyclics that utilize nitroreductase enzyme systems for their activation. In this article, recent developments of anticancer prodrug design are described with a particular emphasis on exploitation of selective metabolic processes for their activation.

Animals↗
PubMed2000

A genetic algorithm for the automated generation of small organic molecules: drug design using an evolutionary algorithm.

Rational drug design involves finding solutions to large combinatorial problems for which an exhaustive search is impractical. Genetic algorithms provide a novel tool for the investigation of such problems. These are a class of algorithms that mimic some of the major characteristics of Darwinian evolution. LEA has been designed in order to conceive novel small organic molecules which satisfy quantitative structure-activity relationship based rules (fitness). The fitness consists of a sum of constraints that are range properties. The algorithm takes an initial set of fragments and iteratively improves them by means of crossover and mutation operators that are related to those involved in Darwinian evolution. The basis of the algorithm, its implementation and parameterization, are described together with an application in de novo molecular design of new retinoids. The results may be promising for chemical synthesis and show that this tool may find extensive applications in de novo drug design projects.

Algorithms↗
PubMed1997

[Epidemiology of designer drug use in Spain].

BACKGROUND: To provide epidemiological information on the extent of design drug use in Spain, the characteristics of users, and the types of substances consumed. MATERIALS AND METHODS: We analyzed two surveys on drug use carried out in 1993 and 1994 (one in the general population older than 15 years and the other in heroin and/or cocaine users who were not in treatment) as well as data on designer drug seizures confiscated by the General Police Headquarters and Ministry of Health laboratories. RESULTS: According to the general population survey, 4.5% of persons 16-40 years of age have tried design drugs at some time, 2.1% more than once, and 0.6% are current users. Design drug use is associated with age of 20-24 years and use of crack (odds ratio [OR] = 28.6), cannabis (OR = 12.5), cocaine (OR = 7.6) or heroin (OR = 3.8). According to the survey of heroin/cocaine users, 25% of cocaine users have used design drugs in the last 30 days, 11% of heroin users, and 18% of those who use both substances. Use is associated with the use of hallucinogens (OR = 4.8), non-use of the injected route (OR = 2), and having been interviewed in recreational areas (OR = 1.8). Police data reflect a stability in the quantities of amphetamines confiscated, a large increase in those of MDMA, and an absence of MDA and MDEA. Ministry of Health laboratories show an increase in confiscations of amphetamines and the presence of MDA, MDMA and MDEA in all years and areas studied, as well as the appearance of MBDB in 1994. CONCLUSIONS: The occasional use of different design drugs has spread to some degree among young people, varies considerably by geographic region, and is associated with the use of other legal and illegal substances, specially stimulants.

3,4-Methylenedioxyamphetamine↗
PubMed2004

Homology-based modelling of targets for rational drug design.

The current status in rational drug design using homology-based models is discussed, with focus on template selection, model building, model verification and strategies for drug design based on model structures. A novel approach for identification of unique binding site features from homology-based models, Protein Alpha Shape Similarity Analysis (PASSA) is described.

Binding Sites↗
PubMed1995

X-ray structures of human neutrophil collagenase complexed with peptide hydroxamate and peptide thiol inhibitors. Implications for substrate binding and rational drug design.

Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases involved in tissue remodeling. They have also been implicated in various disease processes including tumour invasion and joint destruction and are therefore attractive targets for inhibitor design. For rational drug design, information of inhibitor binding at the atomic level is essential. Recently, we have published the refined high-resolution crystal structure of the catalytic domain of human neutrophil collagenase (HNC) complexed with the inhibitor Pro-Leu-Gly-NHOH, which is a mimic for the unprimed (P3-P1) residues of a bound peptide substrate. We have now determined two additional HNC complexes formed with the thiol inhibitor HSCH2CH(CH2Ph)CO-L-Ala-Gly-NH2 and another hydroxamate inhibitor, HONHCOCH(iBu)CO-L-Ala-Gly-NH2, which were both refined to R-values of 0.183/0.198 at 0.240/0.225-nm resolution. The inhibitor thiol and hydroxamate groups ligand the catalytic zinc, giving rise to a slightly distorted tetrahedral and trigonal-bipyramidal coordination sphere, respectively. The thiol inhibitor diastereomer with S-configuration at the P1' residue (corresponding to an L-amino acid analog) binds to HNC. Its peptidyl moiety mimics binding of primed (P1'-P3') residues of the substrate. In combination with our first structure a continuous hexapeptide corresponding to a peptide substrate productively bound to HNC was constructed and energy-minimized. Proteolytic cleavage of this Michaelis complex is probably general base-catalyzed as proposed for thermolysin, i.e. a glutamate assists nucleophilic attack of a water molecule. Although there are many structural and mechanistic similarities to thermolysin, substrate binding to MMPs differs due to the interactions beyond S1'-P1'. While thermolysin binds substrates with a kink at P1', substrates are bound in an extended conformation in the collagenases. This property explains the tolerance of thermolysin for D-amino acid residues at the P1' position, in contrast to the collagenases. The third inhibitor, HONHCOCH(iBu)CO-L-Ala-Gly-NH2, unexpectedly binds in a different manner than anticipated from its design and binding mode in thermolysin. Its hydroxamate group obviously interacts with the catalytic zinc in a favourable bidentate manner, but in contrast its isobutyl (iBu) side chain remains outside of the S1' pocket, presumably due to severe constraints imposed by the adjacent planar hydroxamate group. Instead, the C-terminal Ala-Gly-NH2 tail adopts a bent conformation and inserts into this S1' pocket, presumably in a non-optimized manner. Both the isobutyl side chain and the C-terminal peptide tail could be replaced by other, better fitting groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2003

Designer drugs: how dangerous are they?

Of the designer drugs, the amphetamine analogues are the most popular and extensively studied, ecstasy (3,4-methylenedioxymethamphetamine; MDMA) in particular. They are used recreationally with increasing popularity despite animal studies showing neurotoxic effects to serotonin (5-HT) and/or dopamine (DA) neurones. However, few detailed assessments of risks of these drugs exist in humans. Previously, there were no methods available for directly evaluating the neurotoxic effects of amphetamine analogues in the living human brain. However, development of in vivo neuroimaging tools have begun to provide insights into the effects of MDMA in human brain. In this review, contributions of brain imaging studies on the potential 5-HT and/or DA neurotoxic effects of amphetamine analogues will be highlighted in order to delineate the risks these drugs engender in humans, focusing on MDMA. An overview will be given of PET, SPECT and MR Spectroscopy studies employed in human users of these drugs. Most of these studies provide suggestive evidence that MDMA is neurotoxic to 5-HT neurones, and (meth)amphetamine to DA neurones in humans. These effects seem to be dose-related, leading to functional impairments such as memory loss, and are reversible in several brain regions. However most studies have had a retrospective design, in which evidence is indirect and differs in the degree to which any causative links can be implied between drug use and neurotoxicity. Therefore, at this moment, it cannot be ascertained that humans are susceptible to MDMA-induced 5-HT injury or (meth)amphetamine-induced DA injury. Finally, although little is known about other amphetamine analogues there are important questions as to the safety of these designer drugs as well, in view of the fact that they are chemically closely related to MDMA and some have been shown to be 5-HT neurotoxins in animals.

Animals↗