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PubMed1995

Modelling of guanine-derivative--protein interaction complexes as a basis of drug design.

In rational drug design the study of protein-ligand-interactions is one of the most important approaches to get knowledge of SAR. On this study N2-Phenylthioguanines were synthesized by Schiemann reaction from thioguanine followed by a substitution of the fluorine by aniline-derivatives. The activity of these HSV1 TK inhibitors was determined by kinetic measurements of thymidine phosphorylation. The N2-Phenylthioguanines gave the same activity as the oxoanalogues. Interaction energies between thymidine and HSV1 TK were measured by microcalorimetry. Results of the measurement showed negative delta G and delta H values which indicates that the binding of the natural substrate occurs spontaneously and is enthalpy driven.

Calorimetry↗
PubMed2006

Drug evolution concept in drug design: 2. Chimera method.

The drug evolution method represents a novel approach towards efficient rational drug design by implementing the drug evolution concept to the creation and development of general chemical libraries with the purpose of allowing the identification of drug candidates with improved odds and lesser costs than the traditional drug design strategies. As another example of successful translation of the biological evolution into chemical evolution, the chimera method comprises the grafting of selected building blocks, identified through a basic search within a drug library, onto the same substitution sites on a rationally chosen scaffold. The method allows the creation of a library containing both drugs and prospective drug candidates without any priorly required knowledge on the pursued disease or molecular target. Two libraries having scaffolds derived from para-aminobenzoic acid and salicylic acid have exemplified the application of the chimera method. The validation of the method has been achieved through the high number of recognized drugs within the library, which exhibit in the same time a wide variety of therapeutic activities and interact with a broad spectrum of molecular targets. The drug-enriched chimera libraries are expected to provide a highly efficient access to novel drug candidates whose unspecified therapeutic effects should be further revealed through high-throughput screening.

4-Aminobenzoic Acid↗
PubMed2005

Metal complexes in medicinal chemistry: new vistas and challenges in drug design.

An overview is presented of selected metal-based pharmaceuticals, either diagnostic or therapeutic, with emphasis on specific attributes and in vivo interactions of these compounds relevant to their use in medicinal applications. Both the advantages and the challenges of this approach are outlined, with possibilities for future developments accentuated.

Chemistry, Pharmaceutical↗
PubMed2000

Mimicking dominant negative inhibition of prion replication through structure-based drug design.

Recent progress determining the structure of the host-encoded prion protein (PrP(C)) and the role of auxiliary molecules in prion replication permits a more rational approach in the development of therapeutic interventions. Our objective is to identify a new class of lead compounds that mimic the dominant negative PrP(C) mutants, which inhibit an abnormal isoform (PrP(Sc)) formation. A computational search was conducted on the Available Chemicals Directory for molecules that mimic both the spatial orientation and basic polymorphism of PrP residues 168, 172, 215, and 219, which confer dominant negative inhibition. The search revealed 1,000 potential candidates that were visually analyzed with respect to the structure of this four-residue epitope on PrP(C). Sixty-three compounds were tested for inhibition of PrP(Sc) formation in scrapie-infected mouse neuroblastoma cells (ScN2a). Two compounds, Cp-60 (2-amino-6-[(2-aminophenyl)thio]-4-(2-furyl)pyridine-3, 5-dicarbonitrile) and Cp-62 (N'1-(¿5-[(4, 5-dichloro-1H-imidazol-1-yl)methyl]-2-furyl¿carbonyl)-4 methoxybenzene-1-sulfonohydrazide), inhibited PrP(Sc) formation in a dose-dependent manner and demonstrated low levels of toxicity. A substructure search of the Available Chemicals Directory based on Cp-60 identified five related molecules, three of which exhibited activities comparable to Cp-60. Mimicking dominant negative inhibition in the design of drugs that inhibit prion replication may provide a more general approach to developing therapeutics for deleterious protein-protein interactions.

Algorithms↗
PubMed2004

Chemistry, pharmacology, toxicology, and hepatic metabolism of designer drugs of the amphetamine (ecstasy), piperazine, and pyrrolidinophenone types: a synopsis.

Designer drugs of the amphetamine type (eg, MDMA, MDEA, MDA), of the new benzyl or phenyl piperazine type (eg, BZP, MDBP, mCPP, TFMPP, MeOPP), or of the pyrrolidinophenone type (eg, PPP, MOPPP, MDPPP, MPPP, MPHP) have gained popularity and notoriety as rave drugs. These drugs produce feelings of euphoria and energy and a desire to socialize. Although in the corresponding drug scene designer drugs have the reputation of being safe, studies in rats and primates in combination with human epidemiologic investigations indicate potential risks to humans. Thus, a variety of adverse effects have been associated with the use/abuse of this class of drugs in humans, including a life-threatening serotonin syndrome, hepatotoxicity, neurotoxicity, and psychopathology. Metabolites were suspected to contribute to some of the toxic effects. Therefore, knowledge of the metabolism is a prerequisite for toxicologic risk assessment. The metabolic pathways, the involvement of cytochrome P450 isoenzymes in the main pathways, and their roles in hepatic clearance are described for designer drugs of different groups. In summary, polymorphically expressed CYP2D6 was the major enzyme catalyzing the major metabolic steps of the studied piperazine- and pyrrolidinophenone-derived designer drugs. However, it cannot be concluded at the moment whether this genetic polymorphism is of clinical relevance.

Amphetamines↗
PubMed2005

Integrating research and development: the emergence of rational drug design in the pharmaceutical industry.

Rational drug design is a method for developing new pharmaceuticals that typically involves the elucidation of fundamental physiological mechanisms. It thus combines the quest for a scientific understanding of natural phenomena with the design of useful technology and hence integrates epistemic and practical aims of research and development. Case studies of the rational design of the cardiovascular drugs propranolol, captopril and losartan provide insights into characteristics and conditions of this integration. Rational drug design became possible in the 1950s when theoretical knowledge of drug-target interaction and experimental drug testing could interlock in cycles of mutual advancement. The integration does not, however, diminish the importance of basic research for pharmaceutical development. Rather, it can be shown that still in the 1990s, linear processes of innovation and the close combination of practical and epistemic work were interdependent.

Biomedical Research↗
PubMedDate not supplied

Rational drug design: the proteinase inhibitors.

Human immunodeficiency virus (HIV) proteinase is a promising target for the rational development of drugs against the acquired immunodeficiency syndrome (AIDS), since this enzyme is necessary for viral maturation, and its inhibition could lead to cessation of viral replication. Rational drug design combines chemical synthesis of compounds with structure determination methods, including protein crystallography. When the crystal structure of the HIV proteinase was determined, many research laboratories began designing drugs that would be effective inhibitors of the enzyme, and many such inhibitors were produced. Once that work was initiated, refined, and completed in the laboratory, other issues, such as specificity and bioavailability, became important. The clinical utility of such compounds is the final and most important consideration. Analysis of many agents for which structural formulas have been determined, and comparison of such formulas, provide valuable lessons for the continuing work on this enzyme and for future programs of rational drug design.

Amino Acid Sequence↗
PubMed2005

Can drug design inhibit abuse?

A recent federal report indicates that prescription drug abuse is now the second leading category of illicit drug use, following marijuana use. Control strategies typically focus on reducing the diversion of prescription drugs from legitimate sources. The proliferation of unregulated Internet sources, however, has rendered control strategies less effective. This study examines a new approach that focuses on reducing abusability through the use of abuse-resistant drug designs. Drugs with and without such designs are compared and abuse levels assessed using multiple sources. In every instance, drugs employing abuse-resistant designs were found to have significantly lower levels of abuse than comparator drugs without such designs.

Clinical Pharmacy Information Systems↗
PubMed1997

Contributions of protein structure-based drug design to cancer chemotherapy.

Protein structure-based drug design (SBDD) uses a knowledge of the molecular structure of a target macromolecule, normally obtained by x-ray crystallography, to design potent, selective inhibitors. This technique has played a major role in the design of a number of drugs that have progressed to clinical trials. Most of these compounds have been developed to treat viral diseases and cancer. In the antiviral area, drugs designed by SBDD have been developed for treatment of influenza and acquired immune deficiency syndrome. Three human immunodeficiency virus-I protease inhibitors that were designed at least partially using the x-ray crystal structure of the target enzyme are now approved for sale in the United States. In the anticancer field, no SBDD-designed drugs have yet progressed to market, but several experimental anticancer agents that were designed from a knowledge of the molecular structure of their target enzyme have advanced to clinical trials, of which at least one has shown clinical activity. The present article discusses the strengths and weaknesses of the SBDD approach, and shows its contributions to cancer chemotherapy by discussing rationally designed inhibitors of thymidylate synthase, purine nucleoside phosphorylase, glycinamide ribonucleotide formyltransferase, and matrix metalloproteases.

Acyltransferases↗
PubMed1995

Progress in anti-HIV structure-based drug design.

The course of drug development for the treatment of HIV-1 infection and AIDS is being revolutionized by high-resolution structures of essential viral proteins. We survey the impact on drug design of the recently elucidated structural knowledge of two essential enzymes, reverse transcriptase and protease, and three new targets, the viral integrase and the gene regulatory protein-RNA interactions, Tat-TAR and Rev-RRE.

Antiviral Agents↗
PubMedDate not supplied

'Designer drugs'. A problem in clinical toxicology.

'Designer drugs' are substances intended for recreational use which are derivatives of approved drugs so as to circumvent existing legal restrictions. The term as popularised by the lay press lacks precision. Contrary to the popular belief that 'designer drugs' are original creations, the majority of these agents are 'borrowed' from legitimate pharmaceutical research. They merely represent the most recent developments in the evolution of mind-altering chemicals. The most extensively studied class of psychoactive compounds is the phenylethylamines (mescaline analogues). This class includes catecholamines, therapeutic agents and numerous illicit derivatives. Subtle alterations of the phenylethylamine molecule give rise to a spectrum of pharmacological properties ranging from pure sympathomimetic stimulation to primarily psychoactive effects. Although most of these compounds are only of historical interest, amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), and 3,4-methylenedioxymethamphetamine (MDMA) continue to be used recreationally. Many deaths have been ascribed to this class of compounds. In overdose the differences between these compounds blur and the clinical presentation is similar to that of amphetamine overdose characterised by tachycardia, hypertension, hyperthermia, diaphoresis, mydriasis, agitation, muscle rigidity, and hyper-reflexia. Death usually results from arrhythmias, hyperthermia or intracerebral haemorrhage. Treatment is aggressive and supportive with careful attention to temperature, blood pressure and seizure control. Synthetic opioid derivatives, which represent the second major class of 'designer drugs', are derivatives of fentanyl (e.g. alpha-methylfentanyl, 3-methylfentanyl) or pethidine (meperidine) and are extremely potent compounds responsible for numerous overdose deaths. Attempts to synthesise pethidine have resulted in the accidental production of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a compound which is metabolised in the brain by the monoamine oxidase system to a toxic intermediate (MPP+) which selectively destroys the sustantia nigra, resulting in the rapid onset of severe Parkinsonian symptoms. Naloxone will antagonise the opiate effects of this drug class, although high doses may be required. Arylhexylamines constitute the third class of 'designer drugs'. The predominant member of this class is phencyclidine (PCP), a derivative of the anaesthetic ketamine. This unique class of psychoactive agents exhibits broad and complex pharmacological effects.(ABSTRACT TRUNCATED AT 400 WORDS)

Chemistry, Pharmaceutical↗
PubMed2002

History and evolution of the pharmacophore concept in computer-aided drug design.

With computer-aided drug design established as an integral part of the lead discovery and optimization process, pharmacophores have become a focal point for conceptualizing and understanding receptor-ligand interactions. In the structure-based design process, pharmacophores can be used to align molecules based on the three-dimensional arrangement of chemical features or to develop predictive models (e.g., 3D-QSAR) that correlate with the experimental activities of a given training set. Pharmacophores can be also used as search queries for retrieving potential leads from structural databases, for designing molecules with specific desired attributes, or as fingerprints for assessing similarity and diversity of molecules. This review article presents a historical perspective on the evolution and use of the pharmacophore concept in the pharmaceutical, biotechnology, and fragrances industry with published examples of how the technology has contributed and advanced the field.

Algorithms↗
PubMed2006

A computational approach to botanical drug design by modeling quantitative composition-activity relationship.

Herbal medicine has been successfully applied in clinical therapeutics throughout the world. Following the concept of quantitative composition-activity relationship, the presented study proposes a computational strategy to predict bioactivity of herbal medicine and design new botanical drug. As a case, the quantitative relationship between chemical composition and decreasing cholesterol effect of Qi-Xue-Bing-Zhi-Fang, a widely used herbal medicine in China, was investigated. Quantitative composition-activity relationship models generated by multiple linear regression, artificial neural networks, and support vector regression exhibited different capabilities of predictive accuracy. Moreover, the proportion of two active components of Qi-Xue-Bing-Zhi-Fang was optimized based on the quantitative composition-activity relationship model to obtain new formulation. Validation experiments showed that the optimized herbal medicine has greater activity. The results indicate that the presented method is an efficient approach to botanical drug design.

Algorithms↗
PubMed2003

The process of structure-based drug design.

The field of structure-based drug design is a rapidly growing area in which many successes have occurred in recent years. The explosion of genomic, proteomic, and structural information has provided hundreds of new targets and opportunities for future drug lead discovery. This review summarizes the process of structure-based drug design and includes, primarily, the choice of a target, the evaluation of a structure of that target, the pivotal questions to consider in choosing a method for drug lead discovery, and evaluation of the drug leads. Key principles in the field of structure-based drug design will be illustrated through a case study that explores drug design for AmpC beta-lactamase.

Algorithms↗
PubMed2002

Application of topological descriptors in QSAR and drug design: history and new trends.

Powerful methodologies for drug design and drug database screening and selection are presently available. Studies relating the structure of molecules to a property or a biological activity by means of statistical tools (QSPR and QSAR studies, respectively) are particularly relevant. An important point for this methodology is the use of good structural descriptors that are representative of the molecular features responsible for the relevant activity. Topological indices (TIs) are two-dimensional descriptors which take into account the internal atomic arrangement of compounds, and which encode in numerical form information about molecular size, shape, branching, presence of heteroatoms and multiple bonds. The usefulness of TIs in QSPR and QSAR studies has been extensively demonstrated, and they have also been used as a measure of structural similarity or diversity by their application to databases virtually generated by computer. In this article we will briefly review the history of TIs, their advantages and limitations with respect to other descriptors, and their possibilities in drug design and database selection. These applications rely on new computational techniques such as virtual combinatorial synthesis, virtual computational screening or inverse QSAR.

Algorithms↗
PubMed1996

On the metabolism and the toxicological analysis of methylenedioxyphenylalkylamine designer drugs by gas chromatography-mass spectrometry.

Designer drugs of the methylenedioxyphenylalkylamine type are increasingly abused. Studies on their metabolism in humans are necessary to develop a reliable gas chromatography--mass spectrometry (GC-MS) screening procedure. Such a method must allow their detection in urine for drug testing in clinical and forensic toxicology. Studies on racemic methylenedioxyamphetamine (MDA), methylenedioxymetamphetamine (MDMA), methylenedioxyethylamphetamine (MDE), benzodioxazolylbutanamine (BDB), and N-methylbenzodioxazolylbutanamine (MBDB) are presented. The metabolites were identified by GC-MS after enzymatic hydrolysis, isolation (pH 4.5 and 8-9), and derivatization (acetylation followed by methylation). The drugs undergo two overlapping metabolic pathways: O-dealkylation of the methylenedioxy group to dihydroxy derivatives followed by methylation of one of the hydroxy groups and successive degradation of the side chain to N-dealkyl and deaminooxo metabolites. MDA, MDMA, and MDE are subsequently metabolized to glycine conjugates of the corresponding 3,4-disubstituted benzoic acids. The hydroxy metabolites are excreted in a conjugated form. Based on these results, a GC-MS procedure was developed for simultaneous screening and identification of these designer drugs and/or their metabolites in urine after acid hydrolysis, isolation at pH 8-9, and acetylation. With use of mass chromatography with the most characteristic fragment ions m/z 58, 72, 86, 150, 162, 164, 176, and 178, the presence of the designer drugs was indicated and the peak underlying spectra could be identified by computerized comparison with reference spectra recorded during the presented studies. The procedure was suitable to detect an abuse of or an intoxication with the studied designer drugs (detection limit 5-50 ng/ml).

3,4-Methylenedioxyamphetamine↗