P-SIFt

We have developed a profile-based approach termed p-SIFt [7] that enables us to describe the conservation of interactions between a set of protein-ligand receptor complexes. The use of profiles provides a sensitive means to compare and contrast multiple inhibitors binding to a drug target. A structural interaction fingerprint profile (p-SIFt) represents the degree to which interactions are conserved across a set of ligand-receptor complexes. The p-SIFt, P(r), is derived from an array, denoted below as b, of SIFt patterns and its derivation from a set of SIFts is shown in Fig. 10.2. 

Fig. 10.2 The procedure used to generate a p-SIFt from a set of SIFts is illustrated in (a). The profile shown corresponds to the p-SI Ft generated from the 93 kinase structures using all seven bits to compute the SIFts shown in (b). The p-SIFt is annotated with a topmost bar delineating the general kinase structural features for that portion of the...

A convenient way to compare directly the p-SIFts is to define a difference profile computed by the direct subtraction of one p-SIFt from another. The differ-... 

Fig. 10.4 The contact-only p-SIFts for ATPg (top), p38 (middle) and CDK2 (bottom) are plotted as a function of PKA residue numbering. The unshaded outline shown in the ATPg panel corresponds to the p-SIFt...

SIFt scoring approach. For p38, the 11ybrid Scoring scheme (p-SIFT to rule out undesirable poses followed by energy scoring function identify and rank the best pose) was found to offer no improvement in enrichment over that obtained from using p-SIFt scoring. 

Fig. 10.7 I integration of SIFt into the structure-based drug design workflow. The experimental structure(s) of a drug target in complex with small molecules are used to generate SIFt and p-SIFt. This is used to filter a...

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