| Abstract
| - Three quasi-dynamic pharmacophore models have been constructed for the complement inhibitorpeptide compstatin, using first principles. Uniform sampling along 5-ns molecular dynamics trajectoriesprovided dynamic conformers that are thought to represent the entire conformational space for nine trainingset molecules, compstatin, four active analogues, and four inactive analogues. The pharmacophore modelswere built using mixed physicochemical and structural properties of residues indispensable for structuralstability and activity. Owing to the size and flexibility of compstatin, one-dimensional probability distributionsof intrapharmacophore point distances, angles, and dihedral angles of different analogues spread overwide and overlapping ranges. More robust two-dimensional distance−angle probability distributions fortwo pharmacophore models discriminated individual analogues in terms of specific distance−angle pairs,but overall failed to identify the active and the inactive analogues as two distinct groups. Two-dimensionaldistance−dihedral angle probability distributions in a third pharmacophore model allowed discrimination ofthe groups of active and inactive analogues more effectively, with the highest-activity analogue havingdistinct behavior. The present study indicates that more stringent structural constraints should be used fora set of structurally similar but flexible peptides, as opposed to organic molecules, to convert dynamicconformers into pharmacophore models. Flexibility is a general aspect of the structure and function ofpeptides and should be taken into account in ligand-based pharmacophore design. However, thediscrimination of activity using multidimensional probability surfaces depends on the peptide system, theselection of the training set, the molecular dynamics protocol, and the selection of the type and number ofpharmacophore points.
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