Structures of drugs

Badger, J., et al. Three-dimensional structures of drug-resistant mutants of human rhinovirus 14. /. Mol. Biol. 

R Wessels, J. Ogorka, G. Schwinger and M. Ulmer, Elucidation of the structure of drug degradation products by on-line coupled reversed phase HPEC-GC-MS and on-line deiivatization , J. High Resolut. Chromatogr. 16 708-712 (1993). 

Datta S, Grant DJW. Crystal structures of drugs advances in determination, prediction and engineering. Nat Rev Drug Discov 2004 3 42-57. 

Anderson AC, Wright DL. The design and docking of virtual compound libraries to structures of drug targets. Curr Comp Aided Drug Des 2005 1 103-27. 

Statistical, Pharmacophore, and Homology Models and Crystal Structures of Drug-Metabolizing Enzymes... 

STATISTICAL, PHARMACOPHORE, AND HOMOLOGY MODELS AND CRYSTAL STRUCTURES OF DRUG-METABOLIZING ENZYMES... 

J.P. Tollenaere, H. Moereels and L.A. Raymaekers, Atlas of Three-Dimensional Structure of Drugs. Elsevier, Amsterdam, 1979. 

Herbette and co-workers [425-428,445] studied the structures of drugs bound to liposomes using a low-angle X-ray diffraction technique. Although the structural... 

The structures of drugs that have proven clinically useful for treatment of hypertension tend to fall into discrete classes according to their mode of action. It is thus usually a safe assumption that a drug containing a guanidine function will show the... 

Fig. 7.8. Chemical structures of drugs for which human in vivo Peff have been determined.

Such a result appears to be of major interest given that neither any classification of compounds, nor any training information was applied to the PCA model. A more detailed inspection of the score plot in Fig. 17.5 indicates that some compounds are misclassified, although experimental evaluation of these compounds revealed problems with their chemical stability or solubility. Thus, it appears that this model can be used to evaluate the false-positive (or false-negative) experiments. Moreover, it can also be used to evaluate the metabolic stability from the 3D structure of drug candidate prior to experimental measurements. 

The macromolecular structure of drugs and the fact that relatively minor structural alterations can potentially have a major influence upon bioactivity are often complicating factors. For example, an immunoassay may be blind to the oxidation of an amino acid residue, or very limited proteolytic processing, although such events can activate or decrease bioactivity. 

Common Extensions of the Basic Stock/Flow Structure of Drug Development... 

To determine the structures of drug compounds or protein molecules using X-ray crystallography, it is necessary to have these compounds or molecules available in crystalline form. For example, when crystals of protein are formed, the protein molecules are arranged in orderly fashions like tiny imaginary cubes stacked on top of each other. Each of these building blocks contains a molecule of protein and is termed a unit cell (Fig. 3.3). 

M ass spectrometry provides a highly specific method for determining or confirming the identity or structure of drugs and raw materials used in their manufacture. 

The effect of certain structural compounds in relation to its activity, duration of action and mechanism can be altered by changing the structure of drugs of known activity. A new product can show different reactions, different relation between the drugs and cell constituents and perhaps even new mechanism of action. 

The first-generation H receptor antagonists have many actions in addition to blockade of the actions of histamine. The large number of these actions probably results from the similarity of the general structure (Figure 16-1) to the structure of drugs that have effects at muscarinic cholinoceptor, a adrenoceptor, serotonin, and local anesthetic receptor sites. Some of these actions are of therapeutic value and some are undesirable. 

Modification of Chemical Structure of Drug The use of a Hammett linear free-energy relationship to investigate the effects of substituents on the rates of aromatic side-chain reactions such as hydrolysis of esters has been alluded to earlier vis-a-vis attainment of optimum stability [9,10]. Degradation of erythromycin under acidic pH conditions is inhibited by substituting a methoxy group for the C-6 hydroxyl as found for the acid stability of clathromycin, which is 340 times greater than that of erythromycin [70]. 

The third variant, the most recent one, was born from the recognition of the importance of the three-dimensional structure of drugs (Cohen, 1985), and has evolved to three-dimensional QSAR (3D-QSAR). Comparative molecular field analysis (CoMFA) is to date the most sophisticated tool in 3D-QSAR (Cramer et al., 1988 Gaillard et al., 1994). 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

The substantial research focus on the crystal structures of drug substances that has developed over the past decade [l-5a,b] has led to extensive interest in any modification of the properties of drug substances whose physical properties are less than desirable. Within this context, the advances being made in the areas of polymorphism and solvatomorph-ism have been amply documented [6-9]. 

D structures of drugs were converted into hydrogen-suppressed molecular graphs, where nodes are labeled with atom types except hydrogens and edges are labeled with bond types. 

A new generation of transdermal drug delivery (TDD) system was developed to contain one or more skin permeation enhancers in the surface adhesive coating layers. This TDD system has been found, experimentally, to release the enhancers to the surface of stratum corneum to modify the skin s barrier properties, prior to the controlled delivery of the active drug. The extent of enhancement in skin permeability appears to be dependent upon the chemical structure of drug to be delivered transdermally as well as the type and the concentration of enhancer used. The mechanism of skin permeation enhancement have been explored and are analyzed in this report. 

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