Proposal of a 3D peptide pharmacophore of muramyl dipeptide-type immunostimulants .2. Computer docking to a model protein binding site

The conformation of the immunostimulant muramyl dipeptide (N-acetylmuramyl-L-Ala-D-iGln, MDP) selected by the application of the CCLUES method (preceding paper) as the best candidate for the bioactive conformation is closely related to one of its parent compound, N-acetylglucosaminyl-beta 1-->4-N-acetylmuramyl-L-Ala-D-iGln-gamma-diaminopimeloyl-D-Ala, when bound to the T4 lysozyme [Kuroki, R. et al. Science 1993, 262, 2030]. A series of active and inactive MDP analogues has been docked to the same binding site and analyzed for site-to-ligand group-group interactions. The docking experiments demonstrate that the binding site qualitatively discriminates between the diastereomers of MDP and between the active and inactive analogues. It therefore appears to be a suitable model of peptide binding to the putative receptor for immunostimulant MDP-type peptides. The conformation of MDP docked to the model binding site is taken for the ab initio calculation (3-21G basis set) of the molecular electrostatic potential that is representative of the 3D electrostatic pharmacophore of the peptide core. Also including the more general structure-activity relations it can be used as a starting point for the design of MDP mimetics.