Designer drug, designed therapy.
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Antibodies↗
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Results for “Drug Design”
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Clinical trials in the evaluation of antiarrhythmic drugs: design, drugs, and double-blind considerations.
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Anti-Arrhythmia Agents↗
Designer drugs.
Designer drugs are synthetic analogs of substances with known psychoactive properties. These analogs are dangerous due to their direct pharmacological effects and the presence of toxic by-products that occur during synthesis. Three groups of designer drugs are reviewed (fentanyl, meperidine, and methamphetamine analogs), and their psychoactive effects and clinical presentations are described.
Designer Drugs↗
Substance abuse: the designer drugs.
Designer drugs, chemically altered compounds derived from federally controlled substances, have become a major cause of addiction and overdose deaths. These drugs include mescaline analogs, synthetic opioids, arylhexylamines, methaqualone derivatives and crack, a new form of cocaine. Sudden changes in mood, weight loss, depression, disturbed sleep patterns, deteriorating school or work performance, marital problems, and loss of interest in friends and social activities may be signs of drug addiction. Life-threatening complications of acute intoxication, such as hyperthermia, seizures, combative and psychotic behavior, and cardiorespiratory collapse, require prompt diagnosis and supportive intervention.
Clinical Protocols↗
Molecular modelling and drug design.
Drug design is a creative act of the same magnitude as composing, sculpting, or writing. The results can touch the lives of millions, but the creator is rarely one scientist and the rewards are distributed differently in the arts than in the sciences. The mechanisms of creativity are the same, i.e., incremental (plodding from darkness to dawn) or sudden (the "Eureka" effect) realization, but both are poorly understood. Creativity remains a human characteristic, but it is directly related to the tools available, especially computer software and hardware. While modelling software continues to mature, very little new has evolved in terms of hardware. Here, we discuss the history of molecular modelling and describe two novel modelling tools, a haptic device and a program, SCULPT, to generate solid molecular models at atomic resolution.
Databases, Factual↗
Metabolism-based drug design and drug targeting.
Even at the early stages of drug discovery and structure-based drug design, the pharmacokinetic, pharmacodynamic and toxicological consequences of drug metabolism cannot be ignored. Drug metabolism is also of interest to medicinal chemists in the design of drugs with controlled, predictable deactivation after achieving the therapeutic objective in prodrug design and in chemical-enzymatic drug targeting. In this review, the authors provide an overview of concepts that can be utilized from drug discovery to pharmaceutical development to overcome problems associated with drug metabolism, or that may be used to take advantage of 'designed-in' metabolic activation to achieve drug targeting.
Journal Article↗
Structure-based design in drug discovery--the application of a peptoid drug design strategy for the development of non-peptide neuropeptide receptor ligands.
Over the last decade the increasing availability of metabolically- stable non-peptide antagonists targeted at neuropeptide receptors has led directly to a more thorough understanding of the role of neuropeptides in mammalian physiology. By far the majority of these non-peptide neuropeptide receptor antagonists thus far disclosed have been developed from leads identified from broad screening of company compound files or natural product collections, and may thus bear little obvious structural resemblance to the endogenous peptide ligand. This review will focus on an alternative structure-based approach to non-peptide neuropeptide receptor ligand design, referred to as the 'peptoid' drug design strategy, in which an appreciation of the structure of the neuropeptide is the key to the success of this approach. The development and current clinical progress of peptoid cholecystokinin and tachykinin receptor ligands that have thus far resulted from this process will be highlighted and used to exemplify the importance of this novel approach.
Journal Article↗
Drug abuse: designer drugs.
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Designer Drugs↗
PLS-based quantitative structure-activity relationship for substituted benzamides of clebopride type. Application of experimental design in drug design.
The advantageous approach of using an experimentally designed training set as the basis for establishing a quantitative structure-activity relationship with good predictive capability is described. The training set was selected from a fractional factorial design scheme based on a principal component description of physico-chemical parameters of aromatic substituents. The derived model successfully predicts the activities of additional substituted benzamides of 6-methoxy-N-(4-piperidyl)salicylamide type. The major influence on activity of the 3-substituent is demonstrated.
Benzamides↗
Rational drug design: making drugs that make a difference.
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Antineoplastic Agents↗
Challenges of cancer drug design: a drug metabolism perspective.
The time course and duration of action of drugs used in cancer chemotherapy are greatly influenced by the molecular and biochemical properties of enzymes associated with their metabolism. Variation in the response of individual patients to cancer chemotherapeutic agents is in large measure due to genetic and environmental factors that impinge on specific enzymes belonging to the two major classes of drug metabolizing enzymes. Current knowledge of the molecular biology and biochemistry of phase I drug metabolizing enzymes (cytochrome P450, flavin-containing and xanthine oxidases, NADPH quinone reductase, and aldehyde and dihydropyridine dehydrogenases), and phase II enzymes (glucuronosyl-, sulfo-, N-acetyl-, and glutathione transferases, and hydrolases) is reviewed briefly. Advances in understanding genetic and environmental factors that influence activities of phase I and phase II pathways of drug metabolism are discussed in the first sections of this review followed by a consideration of the influence of drug metabolism on the actions of agents currently used in the treatment of cancer. Emphasis is given to drugs that have recently been introduced into the armamentarium of cancer chemotherapy including: inhibitors of chromatin function, target-based inhibitors of signal transduction and cyclin-dependent kinases, and angiogenesis inhibitors acting on metalloproteinases, epithelial cell growth, angiogenesis stimulation, and endothelial-specific integrins.
Angiogenesis Inhibitors↗
Mathematical programming assisted drug design for nonclassical antifolates.
A concept from optimization theory, specifically, mathematical programming, is proposed for designing drugs with desired properties. The mathematical programming formulation is solved to obtain the optimal descriptor values, which are employed in the Cerius(2) modeling environment to infer the optimal lead candidates, in the sense that they exhibit both high selectivity and activity while ensuring low toxicity. It has been observed that unique substituent groups and their molecular conformations are responsible for attaining the goal of simultaneous high selectivity and activity. Both linear and nonlinear quantitative structure activity relationships (QSARs) have been developed for use in the proposed approach. A comparative study of these models is done, and it is shown that the QSARs are well represented by nonlinear models. The proposed mathematical programming strategy has been demonstrated for a class of nonclassical antifolates for Pneumocistis carinii and Toxoplasma gondii dihydofolate reductase. Some of the potential leads found in this study have biological properties similar to those in the open literature. We believe the technique proposed is general and can be applied to other structure based drug design.
Algorithms↗
New approaches to rational drug design.
Rational drug design has emerged as a powerful technique. In this review, three new developments in rational drug design are explored. These developments include new methods to find binding sites for small molecules on the surface of a protein, the suggestion that the protein environment may change the shape of a protein sufficiently to alter drug design, and the use of data emerging from structural genomics in drug design. Although these are three new and distinct areas, the insights derived from these studies suggest a reason for the observation that similar drugs do not always bind to a protein in the same manner.
Binding Sites↗
A new molecular simulation software package--Peking University Drug Design System (PKUDDS) for structure-based drug design.
We present a comprehensive molecular simulation program package, the Peking University Drug Design System (PKUDDS), which runs on personal computers. PKUDDS has been developed mainly for computer-aided drug design using the methods of two-dimensional quantitative structure-activity relationships, three-dimensional quantitative structure-activity relationships, molecular docking, and database screening. This study presents an overview of its functionality, especially of methods developed in our group. PKUDDS uses genetic algorithms in molecular docking, conformational analysis, and quantitative structure-activity relationships as the most useful optimization technique. A user-friendly graphical interface provides easy access to many functions of PKUDDS. We report some examples of our considerable research using PKUDDS.
Antineoplastic Agents↗
Computational approaches to model ligand selectivity in drug design.
To be effective, a designed drug must discriminate successfully the macromolecular target from alternative structures present in the organism. The last few years have witnessed the emergence of different computational tools aimed to the understanding and modeling of this process at molecular level. Although still rudimentary, these methods are shaping a coherent approach to help in the design of molecules with high affinity and specificity, both in lead discovery and in lead optimization. It is the purpose of this review to illustrate the array of computational tools available to consider selectivity in the design process, to summarize the most relevant applications, and to sketch the challenges ahead.
Amino Acid Sequence↗
[An introduction to the computer-aided structure-based drug design--applications of bioinformatics to drug discovery].
Computer-aided drug design methods are effective tools for drug discoveries. It is only small number of compounds that are required to be synthesized in practice, if the computer-aided drug design methods are used to predict the activities of the compounds. The methods are based on the interaction theory between drugs and their target proteins. Steric, electrostatic and hydrophobic complementarities are important in the interaction between the drug and the target protein. When three-dimensional structures of target proteins are known, the method is called as a structure-based drug design, while in case that the structures are unknown, a ligand-based drug design approach is employed for the computer-aided rational drug design. In the computer-aided structure-based drug design, it is important to build up the three-dimensional structure of drug-protein complex and to calculate a binding affinity of the drug to the protein. A molecular dynamics/free energy calculation is one of the most powerful tools to predict the binding affinity of a ligand molecule, when the three-dimensional structure of the drug-protein complex is available. The molecular dynamics/free energy calculation has been able to evaluate the binding affinities of a lot of ligand molecules to the target proteins successfully.
Computational Biology↗
[The molecular patho-pharmacological studies for novel drug design by a principle of drug action in Japanese traditional Sino-medicine system].
In this study we carried out the pharmacological elucidation of the principle of drug action in the Japanese traditional Sino-medicine system, which could have contributed to the modern pharmacology and therapeutics through the discovery of a novel drug design and a new mechanism of drug action. The aim of this study was to focus on the elucidation of the supporting moiety in the drug design for the drug having affinity for a patho-receptor using a quite unique strategy and a new approach based on the natural products, Japanese traditional Sino-medicines relating to disease state, because of enormous clinical experiences with a long history. The characteristics of the pharmacological effects of Japanese traditional Sino-medicines were experimentally demonstrated by the following three key compartments, 1) the combined effect of drugs, 2) the selective activity of drugs to the disease state, 3) the possibility of individual symptomatological patterns (sho) evaluated by autonomic and immuno-pharmacological components. The success of the investigation on the principle of drug action of Japanese traditional Sino-medicines induced not only to obtain many novel compounds and unknown new mechanisms of drug action, but also to find a new salivary peptide for anti-hyperglycemics and a fresh mechanism of ACh receptor desensitization in neuromuscular synapse in the modern pharmacology. The results have brought the interchangeability of Japanese traditional Sino-medicine system to modern medicinal sciences, as described in the following contents, I. On the elucidation of a principle of drug action in the Japanese traditional Sino-medicine system. II. On the developmental frontier of drug design based on Japanese traditional Sino-medicines. III. On the interchangeability between the Japanese traditional Sino-medicine system and the modern medicinal sciences.
Animals↗
Rational drug design approach for overcoming drug resistance: application to pyrimethamine resistance in malaria.
Pyrimethamine acts by selectively inhibiting malarial dihydrofolate reductase-thymidylate synthase (DHFR-TS). Resistance in the most important human parasite, Plasmodium falciparum, initially results from an S108N mutation in the DHFR domain, with additional mutation (most commonly C59R or N51I or both) imparting much greater resistance. From a homology model of the 3-D structure of DHFR-TS, rational drug design techniques have been used to design and subsequently synthesize inhibitors able to overcome malarial pyrimethamine resistance. Compared to pyrimethamine (Ki 1.5 nM) with purified recombinant DHFR fromP. falciparum, the Ki value of the m-methoxy analogue of pyrimethamine was 1.07 nM, but against the DHFR bearing the double mutation (C59R + S108N), the Ki values for pyrimethamine and the m-methoxy analogue were 71.7 and 14.0 nM, respectively. The m-chloro analogue of pyrimethamine was a stronger inhibitor of both wild-type DHFR (with Ki 0.30 nM) and the doubly mutant (C59R +S108N) purified enzyme (with Ki 2.40 nM). Growth of parasite cultures of P. falciparum in vitro was also strongly inhibited by these compounds with 50% inhibition of growth occurring at 3.7 microM for the m-methoxy and 0.6 microM for the m-chloro compounds with the K1 parasite line bearing the double mutation (S108N + C59R), compared to 10.2 microM for pyrimethamine. These inhibitors were also found in preliminary studies to retain antimalarial activity in vivo in P. berghei-infected mice.
Animals↗