R-group descriptor

Figure 6.15 Examples of topological descriptors calculated on backbone and R groups of three bidentate ligands. The broken arrows on the left indicate the minimum Pn-P2 connectivity path (Dt) and the second Pn-P2 path (D2). The dotted arrows indicate freely rotating bonds. The R group descriptor SAMR<3 pertains to the sum of the mass units of atoms that are connected within three bonds of the ligating P atoms.

R-group descriptor, 2,147 random Forest, 2,136,151 rare event, 3,140... 

Sets of substituent pairs of 418 bioisosteric fragments from Bioster 98.1 were used for the validation of the newly defined R-group descriptors, characterizing the physicochemical properties of ring substituents, to (dis)similarity estimation [58]. 

Holliday, J.D., Jelfs, S.P., Willett, P., and Gedeck, P. (2003) Calculation of intersubstituent similarity using R-group descriptors. Journal of Chemical Information and Computer Sciences, 43, 406-411. 

However, perhaps a more rational approach is to characterize mined fragments using computational parameters that have been correlated with being able to identify bioisosteres [19], which was covered in Chapter 7. An alternative approach to using these types of mined fragments is from Holliday et al. [20] using R-group descriptors (see below). 

The R-group descriptor from Holliday et al. [20] is a further example of a topological pharmacophore fingerprint. However, this approach characterizes a distribution of pharmacophoric properties at topological distances from an attachment point. 

A key advantage of the Free-Wilson method over standard descriptors-based QSAR techniques is the estimation of activity contribution for individual R-group structures that are readily interpretable to medicinal chemists. 

R,S)- descriptors can be assigned to prochiral centres in more symmetrical molecules by a simple extension of the sequence rule. For example, in 1,3-cyclobutanediol the OH group at each centre has priority 1 and the H atom priority 4. 

Amino acids (in general) are chiral only the L form is found in proteins, although the D form of alanine is an important component of bacterial cell walls. All amino acids are chiral except glycine. The L/D descriptor is an old fashioned version of the S/R descriptor, and almost all amino acids are the (S)-isomer because the R group (not to be confused with an (R) descriptor ) is priority three. Only cysteine is an exception to this rule, because its R side group is -CH2SH, which has higher priority than COOH. The L/D descriptors come from the CO-... 

R-N law if you place the hydrogen behind the chiral centre, and count round from the COOH group, to the R group, to the NH2 group, this goes anticlockwise, and for similar reason to the R/S descriptor, this means it s the L isomer. The D-isomer goes clockwise. 

The pharmacophore point types used to derive PharmPrint descriptors are hydrogen-bond acceptor (A), hydrogen-bond donor (D), sites of formal negative (N) and positive (P) charges, and hydrophobic (H) and aromatic (R) groups. A seventh type (X) is used to label all the atoms that are not assigned to any PPP type. 

Similar descriptors along with indicator variables for the other R groups on 36 provide the other variables used. 

The application of this topological fingerprint to a database of more than 700 000 structural fragments resulted in more than 2200 experimentally observed bioisos-teric R-groups, cores, and linkers from the Bioster database [22]. The descriptor was also optimized to increase the separation between experimentally observed bioisos-teric pairs and pairs selected at random. 

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