The conformational analysis of two prolyl-endopeptidase (PEP) inhibitors was performed. A molecular mechanics based random conformational search showed that 4-phenyl-butyryl-prolyl-pyrrolidine is U-shaped in most low-energy conformations. The results were compared with semiempirical AM1 calculations. In contrast, the molecule octanoyl-prolyl-pyrrolidine has a linear alkyl-chain, although the U-shaped conformations, required for the same mechanism of action, can be easily attained. The results of conformational analyses were compared with those of NMR measurements. The common pharmacophore for these and several other PEP inhibitors was derived.
- Conformational search
- PEP inhibitors
- Propyl-endopeptidase inhibitors
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