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Abstract

The de novo design program Skelgen has been used to design inhibitor structures for four targets of pharmaceutical interest. The designed structures are compared to modeled binding modes of known inhibitors (i) visually and (ii) by means of a novel similarity measure considering the size and spatial proximity of the maximum common substructure of two small molecules. It is shown that the Skelgen algorithm generates representatives of many inhibitor classes within a very short time and that the new similarity measure is useful for comparing and clustering designed structures. The results demonstrate the necessity of properly defining search constraints in practical applications of de novo design.

Scaffold‐Hopping Potential of Ligand‐Based Similarity Concepts

“…Different virtual-screening concepts have been proposed for scaffold hopping. [4] These include three-dimensional pharmacophore models, [9,15] pseudoreceptors, [16] protein-structure-based de novo design, [1,17] and ligand-based similarity searching. [18] Typically, rapid similarity searching is based on the comparison of descriptor vectors rather than on the explicit alignment of molecules to a reference and can thus be efficiently applied to screening large datasets.…”

Dock around the Clock – Current Status of Small Molecule Docking and Scoring

“…As a consequence molecular docking schemes have been developed that incorporate different aspects of protein flexibility. These include, e.g., the early attempt of soft docking [82], the hinge-bending concept [83,84], the limited conformational freedom approach [19, 85 -89], the simulated annealing approach [90,91], the relaxed complex method [92,93], and a process used for incorporating receptor structural changes involving complex minimization from different initial positions of the ligand in the binding site [94]. Nowadays many software companies have addressed the topic of protein flexibility and improved their core docking procedures or developed additional protocols or software solutions on top of them.…”

“…Each molecule is then prioritized according its calculated score based on its docked binding mode. A comprehensive validation study on the practical use of automated de novo design confirms that de novo design techniques play a major role in the identification of innovative new chemotypes [142]. Even in the absence of receptor information de novo design has been successfully applied using HMs [143,144] or pseudoreceptors [145].…”

Ligand Docking and Design in a Flexible Receptor Site

“…The de novo design algorithm Skelgen [20] was extended to integrate dynamic receptor flexibility by allowing an additional transition type corresponding to side-chain mobility. Side-chain conformers are represented by c torsion angles, and these are randomly modified to give the best induced fit between the evolving ligand and the flexible site.…”