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Table 3 SAR data from CCK/gastrin derivatives and their correspondence to our model

From: Structural studies on radiopharmaceutical DOTA-minigastrin analogue (CP04) complexes and their interaction with CCK2 receptor

Residue SAR data from CCK/gastrin derivatives Correspondence to the in silico prediction SAR ref.
C-terminal tetrapeptide 1. C-terminal sequence in cholecystokinins and gastrins is a condition necessary and sufficient for high affinity towards the receptor
2. Even a fragment as small as a tetrapeptide H-Trp-Met-Asp-Phe-NH2 (CCK-4) exhibits relatively good binding
The C-terminus entering the binding cavity in the helical bundle (as found in our model) fits this observation [27, 48]
Phe−1 Exchange for a wide array of aromatic and aliphatic side chains is well-tolerated; it can even bring about a significant increase of affinity The side chain in the “aromatic box” forms non-specific dispersive interactions, relatively bulky aliphatic or aromatic groups could be adapted [49, 50]
Asp−2 Direct interaction of Asp with His207ECL2 been proposed earlier based on experimental results Direct agreement—the charged side-chain points to His207ECL2 [51]
Met−3 1. The receptor affinity is indifferent to exchange for an equally long hydrophobic side chain of norleucine
2. Less favorable but still tolerable seems the introduction of phenylalanine, phenylglycine, or cyclohexylglycine
3. Short Ala side chain in this position brings about a notable decrease in affinity
4. The drop is dramatic upon introduction of charged ornithine or glutamic acid side chains (similar to Met regarding the length)
The side chain lies in a rather non-polar area with some free space around it allowing for example accommodation of a phenyl ring but not of the charged side chains [50, 52]
Trp−4 1. A change in stereochemistry results in a binding decrease
2. This position is quite tolerant to some (but not all) substitutions for other l-aminoacids with bicylic aromatic side chains
3. Monocyclic aromatics like phenylalanine derivatives cause a decrease in affinity
1. Other side-chain directionality of D-Trp−4 analogues should require adaptation of a completely different binding mode
2. Smaller cycles should give less tight matching and some lowering of the affinity
[50, 53]
[53, 54]