Structurally diverse compounds

Figure 11.6 Schematic representation of the GABAa receptor complex. Examples of the many structurally diverse compounds that act at different sites on the receptor (see text for details). Picrotoxinin, the active component of picrotoxin, and TBPS act as non-competitive antagonists. The barbiturates, steroids and anaesthetics are positive allosteric modulators, as are the benzodiazepine site ligands shown, with the exception of DMCM (negative allosteric modulator) and flumazenil (benzodiazepine site antagonist)...

Other groups of biota are able to bring about transformation of structurally diverse compounds and limited investigations have revealed the metabolic potential of taxonomically diverse eukaryotic organisms ... 

Calculated molecular descriptors including H-bond parameters were used for QSAR studies on different types of permeabiUty. For example, the new H-bond descriptor characterizing the total H-bond ability of a compound, was successfully appUed to model Caco-2 cell permeability of 17 drugs [30]. A similar study on human jejunal in vivo permeabiUty of 22 structurally diverse compounds is described in Ref. [62]. An exceUent one-parameter correlation of human red ceU basal permeabiUty (BP) was obtained using the H-bond donor strength [63] ... 

Oostenbrink, C. van Gunsteren, W. F., Free energies of ligand binding for structurally diverse compounds, Proc. Natl Acad. Sci. USA 2005,102, 6750-6754... 

These structurally diverse compounds exhibit a range of biological activities in vitro that may explain their potential health-promoting properties, including antioxidant and anti-inflammatory effects and the induction of apoptosis (Hooper and others 2008). Most of the recent interest in flavonoids as health-promoting compounds is related to their powerful antioxidant properties. The criteria to establish the antioxidant capacity of these compounds is based on several structural characteristics that include (a) the presence of o-dihydroxyl substituents in the B-ring (b) a double bond between positions 2 and 3 and (c) hydroxyl groups in positions 3 and 5. 

The first application of a computational method to select structurally diverse compounds for purchase started in 1992 at the Upjohn Company, which predated the formation of Pharmacia Upjohn by about three years. The basic approach selected compounds using a method based upon maximum dissimilarity and was implemented using SAS software [11]. This later evolved into the program Dfragall, which was written in C and is described in Section 13.6.3. Basically, a set of compounds that is maximally dissimilar from the corporate compound collection is chosen from the set of available vendor compounds. Early versions of the process relied solely on diversity-based metrics but it was found that many nondrug like compounds were identified. As a result, structural exclusion criteria were developed to eliminate compounds that were considered unsuitable for... 

Histone deacetylases are linked to the pathogenesis of malignancy from a mechanistic perspective. The capacity of HDAC inhibitors (HDACi) to interfere with the enzyme fimction has led to the observed prechnical and clinical activity in cancer therapy. Although the exact mechanism of anti-tumor activity is not fully elucidated, various cellular pathways have been shown to be involved. From the first chnical trials involving HDACi with short chain fatty acids to the newer generation hydroxamic acid derivatives and cychc tetrapeptides, a number of structurally diverse compounds have made the transition from the laboratory to the chnical arena. For purposes of this part of the discussion, HDACi are arbitrarily divided into the hydroxamates and nonhydroxamates. 

De Buck, S.S., Sinha, V.K., Eenu, L.A., Gilissen, R.A.H.J., Mackie, C.E. and Nijsen, M.J. (2007) The prediction of drug metabolism, tissue distribution, and bioavailability of 50 structurally diverse compounds in rat using mechanism-based absorption, distribution, and metabolism prediction tools. Drug Metabolism and Disposition The Biological Fate of Chemicals, 35, 649-659. 

Combinatorial chemistry is both the philosophical and the practical method with which to create structurally diverse compound libraries. Combinatorial chemistry is defined as that branch of synthetic organic chemistry that enables the concomitant synthesis of large numbers of chemical variants in such a manner as to permit their evaluation, isolation, and identification. Combinatorial chemistry affords techniques for the systematic creation of large but structurally diverse libraries. From a technical perspective, there are several avenues of approach to library creation ... 

A variety of structurally diverse compounds is used to eradicate or at least reduce the numbers of helminthic parasites in the intestinal tract or tissues of the body. The search for antihelminthics has been somewhat less systematic than for other microbial pathogens. Most of these agents were discovered by traditional screening programs their mechanisms of action at a molecular level are frequently unknown. 

Solubility-Partition Coefficient Relationships A critical review on the applicability of empirically derived solubility -Kow models has been given by Yalkowsky et al. [24], Isnard and Lambert [26], Lyman [1], and Muller and Klein [27]. Equations 10.4.3 to 10.4.5 are examples of solubility-Kow models. Isnard and Lambert developed a model based on 300 structurally diverse compounds. The model equation for liquids (Tm < 25°C) is... 

Method of Meylan and Howard Meylan and Howard [9] expanded the bond contribution method of Hine and Mookerjee. Based on 345 compounds they derived bond contributions for 59 different bond types. Their method has been validated with an independent set of 74 structurally diverse compounds, obtaining a correlation coefficient of 0.96. Their method also needs correction factors for several structural-substructural features. This method has been implemented into a Henry s law constant program performing AWPC (25°C) estimations from SMILES input [15]. 

Quantitative relationships between Kow and Csw have been reviewed by Isnard and Lambert [11]. These authors developed a model based on 300 structurally diverse compounds. The model equation for liquids (Tm < 25°C) is... 

In eq. 14.3.2, 1xv is the index for the heteroatom-containing molecule and (1Xv) p is the index for the corresponding, nonpolar (np) hydrocarbon equivalent. Bahnick and Doucette [20] demonstrate the calculation of these descriptors for 2-chloroacetani-lide. A ]xv accounts for nondispersive molecular interaction. Testing this model on a validation set of 40 structurally diverse compounds resulted in a standard deviation for the experimental versus estimated values of 0.37. The comparison of this value with the standard error of estimate (5 = 0.34) from the regression model suggests this model can be used confidently within the range of these structures. 

In contrast to all other examples mentioned in this review, the structurally diverse compounds derived from the enc cluster have either been accessed by... 

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