Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set. File list (3) download file view on ChemRxiv manuscript.pdf (4.23 MiB) download file view on ChemRxiv supplementary.pdf (0.92 MiB) download file view on ChemRxiv tables.zip (5.99 KiB)

Recent progress in the synthesis of water-soluble phosphine ligand systems and their corresponding 99mTc complexes prompted the development of a new bifunctional chelating agent (BFCA) based on a tetradentate dithiadiphosphine framework (P2S2-COOH). The detailed synthesis of this new BFCA is described here. The corresponding 99mTc complex, 99mTc-P2S2-COOH, can be formed in >95% yield. To demonstrate the potential of this chelate to efficiently label peptides, 99mTc-P2S2-COOH was coupled to the N-terminal region of the truncated nine-amino acid bombesin analogue, 5-Ava-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 [BBN(7-14)], to form 99mTc-P2S2-BBN(7-14). Conjugation to the peptide was performed in borate buffer (pH 8.5) by applying the prelabeling approach in yields of >60%. In competitive binding assays, using Swiss 3T3 mouse fibroblast cells against [125I-Tyr4]bombesin, Re-P2S2-BBN(7-14) exhibited an IC50 value of 0.8 +/- 0.4 nM. The pharmacokinetic studies of 99mTc-P2S2-BBN(7-14) and its ability to target tissue expressing gastrin-releasing peptide (GRP) receptors were performed in normal mice. The 99mTc-P2S2-BBN(7-14) exhibited fast and efficient clearance from the blood pool (0.6 +/- 0.1% ID, 4 h postinjection) and excretion through the renal and hepatobiliary pathways (56.4 +/- 8.2 and 28.1 +/- 7.9% ID, 4 h postinjection, respectively). Significant uptake in the pancreas was observed (pancreatic acini cells express bombesin/GRP receptors), producing pancreas:blood and pancreas:muscle ratios of ca. 22 and 80, respectively, at 4 h postinjection.

Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br>

The nucleophile-assisted ring-opening reaction of phthalimides 1 has been studied. The reaction of phthalimides 1 with 0.5 equiv of hydrazine produced the novel bisphosphonates 2 in near quantitative yields whereas with 10-fold excess of hydrazine, diethyl aminoalkylphosphonates 3 was formed in 75% yields. The reaction of phthalimide 1b with 3-(aminopropyl)phosphine resulted in a novel compound 4a containing a PIII hydride and a PV phosphonate within the same molecule. In addition, the reaction of 1b with 2-aminoethanol and 2-aminoethanethiol resulted in the formation of new phosphonates 4b,c. The reaction of bisphosphonates 2 with LiAlH4 in THF at 0 °C selectively reduced the phosphonate groups producing corresponding air-stable primary bisphosphines 6 in 80% yields. Further, the formylation of bisphosphines 6 under very mild conditions using 37% aqueous formaldehyde produced the corresponding novel water-soluble bisphosphine chelating agents 7 in near quantitative yields. All the new compounds have been characterized by 1H, 13C, 31P NMR, IR spectroscopy and mass spectrometry.