Proposal of a 3D peptide pharmacophore of muramyl dipeptide-type immunostimulants. Conformational search of active and inactive analogues

The CCLUES method [Pristovsek et al. J. Chem. Inf: Comput. Sci. 1995, 35, 633] is further refined; the set of 42 candidates for the bioactive conformation of the immunostimulator muramyl dipeptide (MDP) obtained in the first run from 1035 originally considered conformations is reduced to the three most probable candidates. The refinement is based on usage of additional information from an inactive and two active analogues: conformations of MDP that superpose well on at least one conformation of the inactive analogue are excluded from the set, while those that do not and additionally superpose well on at least one conformation of the active analogues become more probable candidates. The choice of a final candidate for the bioactive conformation is based on accessibilities of the chemical groups most important for binding to the putative receptor and values of energies calculated with explicit water molecules; the energies of the candidate conformations which differ up to 15 kcal/mol from the lowest-energy conformation in vacuo are virtually equalized by the effects of the aqueous medium.