Biophores

Lebens-ordming,/. regimen, diet, -prozesa, m. vital process, -saft, m. vital fluid (Bot.) latex, -substanz, /. vital substance, -tatig-keit, /. vital activity, -trager, m. (Biol.) biophore. 

The CASE approach is quite different. CASE decomposes a molecule into all possible fragments from two to ten heavy (nonhydrogen) atoms. With a statistical technique, these are then classified into biophores (allied to toxicity) and biophobes (not allied to toxicity). These are then combined into an equation ... 

The multiphore method concepmalizes a dmg as being constmcted in a modular fashion from bioactive subunits, or biophores. Since a dmg is invariably composed of many biophores, it is a multiphore. The most important biophore within the dmg stmcture is the pharmacophore, the subset of atoms within the dmg that permits energetically favorable binding to the receptor site with the elucidation of a subsequent beneficial biological response. Other portions of the molecule determine the metabolic and toxicological properties of the dmg these are the metabophores and toxicophores, respectively. 

In creating synthetic routes for the development of drug molecules, the synthetic chemist wants to create a molecular entity in which functional groups (carbonyls, amines, etc.) are correctly positioned in three-dimensional space this will enable the creation of functional biophoric fragments such as the pharmacophore. The synthetic chemist has ten general classes of reactions available for such synthetic tasks ... 

Klopman et al. DB 1-26 Biophores (degrad. Training (DB1) n = 283 (BIODEG chem.) Correctly... 

Family Target No. of Biophore model CoMFA model... 

The biophores present in colchicinoids highlighted the relevant role of the Cl and CIO methoxy groups and suggested that the size of the substituent at C7 scarcely influenced the interaction of colchicinoids with tubulin, as it was not included in any biophore. 

Chart 2 Biophores present in colchicinoids, podophyllotoxins and combretastatins among those identified as relevant for the activity of CSI... 

Concerning combretastatins, the biophores involving dihydrocombretastatins and combretastatin A-2 analogues mainly indicated the importance of the two carbon bridge, whereas the single CA4 biophore was unable to efficiently describe the activity of CA4 analogues. 

QSAR CSI encompassing several structural classes Biophores for colchicinoids, podophyllotoxins and combretastatins, indicating the main structural features responsible for the activity of compounds [25]... 

Structural features that promote biological activity are sometimes called biophores. They are divisible into pharmacophores and toxicophores. Pharmacophores impart desirable properties on a molecule (e.g., pharmacological activity or a particular fragrance). Toxicophores are responsible for undesirable effects such as toxicity (e.g., mutagenicity and skin sensitization). The same molecule can have more than one descriptor that can act as both a pharmacophore and a toxicophore in the same or different biological systems. Examples here are the toxic side effects of anti-cancer drugs and the use of Warfarin, a commercially available rat poison, to help reduce the formation of blood clots in human heart disease. 

Other structural features can reduce biological activity, and these may be termed biophobes or modifiers. An example of a biophobe is a bulky substituent that reduces the effects of an adjacent biophore by steric hindrance. 

The MultiCASE system has been used to identify a common 6-A unit biophore on a range of hormonally active chemicals with estrogenic activity that act as endocrine disruptors. This structural feature is a spacer biophore that is thought to be involved in the molecules binding to the estrogen receptor and is found on the standard estrogenic chemical, 17-beta-estradiol (see Combes, 2000). Other examples of molecules possessing this biophore include 4-hydroxytamoxifen, 2-chloro-4-hydroxybiphenyl, 3,4-dihydroxyfluorene, and 2,2-(fcE-4-hydroxyphenyl-1,1,1 -trichloroethane). 

Biophores of some tubulin inhibitors were identified by CASE on molecules such as colchicine, podophyllotoxin, and dihydrocombrestatin (see Combes, 2000). These chemicals might act as nongenotoxic carcinogens by being able to bind to tubulin, inducing phenomena such as aneuploidy. 

Rosenkranz et al. have also identified a total of 13 different CASE biophores and 7 biophobes for Draize eye irritation (Rosenkranz et al., 1998). These included structural features on 2,4-dihydroxybenzoic acid and sodium lauryl sulphate. In the case of a quantitative prediction of the eye irritation potential of 2-methylbutyric acid, the ocular irritation potential of the chemical was predicted to be high and was assigned a value of 49 CASE units. 

In the second step of the prediction a new molecule is entered into MultiC ASE, then the program evaluates this molecule against this organized dictionary and the appropriate QS ARs it has created and makes a prediction of the toxicological activity of the molecule for the corresponding endpoint. To do this, MultiCASE identifies all relevant biophores and biophobes of the unknown molecule, combines these into an equation and calculates the toxicological activity expressed in... 

The scale of CASE units has linear range from 10-99 and normally chemicals with an assigned value of 10-19 are inactive, 20-29 have marginal activity and 30-99 are moderate active, active, very active and extremely active. The system is also capable for identifying fragments that act as modifiers to the activity of each biophores class (Greene 2002). 

Structure Evaluating) was first developed before the MultiCASE system. It uses the same technology but differs in some ways. The major algorithmic difference in MultiCASE is the use of hierarchy in the selection of descriptors, leading to the concept of biophores and modulators. Another important difference is that only with MultiCASE new internal proprietary data can be used to create new databases. 

From QSAR studies of several hundreds of DHPs, seven DHPs were found to be very active. From these predictions, manidipine (CV-4093) (56), a newly synthesized DHPs calcium channel blocker, was predicted to be an extremely active MDRR agent. The probability for the DHP to show MDRR activity is very high (99%), owing to the presence of several biophores [102]. 

Predict toxicity/activity on the basis of key biophores required for activity... 

Fig. 30 Apex3D QSAR models of thiazolidines (Table 21) for their activity against Cryptococcus neoformans (CN) (Eq. 40), Tricophyton mentagrophyte (TM) (Eq. 41), and Aspergillus fumigatus (AE) (Eq. 42). In the molecular superimposition, circles identified with arrows represent the locations of the biophoric centers (BC)...

Fig. 31 A composite representation of the thiazolidines superimposition pattern corresponding to Eqs. 40-42 in 2D-structure space. Annotations in italic capital letters A and B stand for the most probable locations of biophoric centers of Eq. 40 (also Eq. 41) and Eq. 42, respectively, and the italic small case a, b and c stand for secondary site locations of Eqs. 40, 41, and 42, respectively. The subscripts of annotations represent the fth cen-ter/site. The most probable atoms for biophoric centers Ai is O, A2 is O or S, A3 is N, Ci is N, C2 is O, and C3 is ring center. Biophore distances A - A2 is 4.7415 A (sd, 0.1831), A2 - A3 is 2.4872 A (sd, 0.1657), Ai - A3 is 3.5598 A (sd, 0.1635), Ci - C2 is 2.2790 A (sd, 0.0279),C2 - C3 is 5.7242 A (sd, 0.3156), and Q - C3 is 3.9253 A (sd, 0.1330). The suffixes pi( r), s, HA, or HD, of a, b, and c indicate the nature of the secondary site, as hydrophobic, steric, hydrogen acceptor or hydrogen donor, respectively. The prefixed negative sign, if any, of a, b, and c indicates the sign of the fth site coefficient in the regression equation. A prime sign on any annotation (lower or upper case) indicates the alternative location of the corresponding site (Reprinted with permission from [191]. Copyright 2003 Wiley)...

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