Analogue database

The 3-D artemisinin analogue database was created with Sybyl 6.2 (Tripos Assoc., St. Louis, MO)154 using the reported crystal structure for artemisinin as a template. The structures were minimized using the Tripos force field in Sybyl 6.2, producing structures close to that of artemisinin. To best describe the aromatic side chains of some analogues, as well as the aliphatic nature of the artemisinin backbone, Gasteiger-Htickel charges were calculated for each of the compounds. 

So to a large extent, 1-D 13C NMR interpretation is a case of matching observed singlets to predicted chemical shifts. These predictions can be made by reference to one of the commercially available databases that we ve mentioned, or it can be done the hard way - by a combination of looking up reference spectra of relevant analogues and using tables to predict the shifts of specific parts of your molecule (e.g., aromatic carbons). We have included some useful 13C shift data at the end of the chapter but it is by necessity, very limited. 

An extensive database has demonstrated that many chemicals that are positive in this test also exhibit mutagenic activity in other tests. There are, however, examples of mutagenic substances, which are not detected by this test reasons for these shortcomings can be ascribed to the specific nature of the endpoint detected, differences in metabolic activation, or differences in bioavailability. On the other hand, factors which enhance the sensitivity of the bacterial reverse mutation test can lead to an overestimation of mutagenic activity. The bacterial reverse mutation test may not be appropriate for the evaluation of certain classes of chemicals for example, highly bactericidal compounds (e.g., certain antibiotics) and those which are thought (or known) to interfere specifically with the mammalian cell replication system (e.g., some topoisomerase inhibitors and some nucleoside analogues). In such cases, mammalian mutation tests may be more appropriate. 

Avenell A, Gillespie WJ, Gillespie LD, O Connell DL. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev. 2005 CD000227. 

A critical issue involved in the creation of these pharmacophores is the determination of the active conformation each compound will retain. Without structural data supporting a specific active conformation, one may be forced to assume that a compound is active in an energetically minimized conformation. In these cases, the molecule s X-ray structure can serve as a template upon which other analogues can be overlaid. Treatment of a database of 202 artemisinin analogues based on the lowest energy conformation assumption has led to a statistically excellent model. 

Within the CoMFA electrostatic map, red contours are displayed in areas where negative charge is associated with increased activity of the database analogues. Red contours are visible near the peroxide bridge, supporting the important role the peroxide plays in activity and near 0-11 (or N-l 1). There are also red contours in... 

Further, there does not exist sufficient data regarding the biological activity for each enantiomer in a racemic mixture of artemisinin analogues. To help define the antimalarial contribution made by each enantiomer, a model was developed in which 40 racemates were placed as single (+)-enantiomers in the original database of 202 compounds. By doing this it was implied that the (-)-enantiomers are as active as their counterpart, and an optically pure compound is not necessary for antimalarial activity. These achiral models have been discussed as 199 (2 A/C.3) and 199 Dock. A database without the racemates, or chiral models 160 (2 A/C.3) and 160 Dock, were also included in our study. Finally, adjustment to an achiral model was attempted in which the activities of the racemates in the 199 (2 A/C.3) model were multiplied by 2, or model 199 (2 A/C.3). In each case, data was subjected to the statistical pis analysis (Table 18). Relative antimalarial activities were predicted for two racemic compounds 421 and 422,155 using these datasets as shown in Tables 19 and 20. 

Figure 1. A simplified plot of the distribution of molecules (symbols) in an idealized two-dimensional chemical property space. The upper plot (a) represents a database consisting of discrete sets of close analogues. The lower plot (b) represents the Optiverse library. (Adapted from ref. 4. Copyright 1996 The Society for Biomolecular Screening, Inc.).

LM Shi, Y Fan, TG Myers, PM O Connor, KD Pauli, SH Friend, JN Weinstein. Mining the NCI anticancer drug discovery databases genetic function approximation for the QSAR study of anticancer ellipticine analogues. J Chem Inf Comput Sci 38 189-199, 1998. 

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