De novo design of molecular architectures by evolutionary assembly of drug-derived building blocks

An evolutionary algorithm was developed for fragment-based de novo design o f molecules (TOPAS, TOPology-Assigning System). This stochastic method aims at generating a novel molecular structure mimicking a template structure. A set of similar to 25,000 fragment structures serves as the building block supply, which were obtained by a straightforward fragmentation procedure a pplied to 36,000 known drugs. Eleven reaction schemes were implemented for both fragmentation and building block assembly. This combination of drug-de rived building blocks and a restricted set of reaction schemes proved to be a key for the automatic development of novel, synthetically tractable stru ctures. In a cyclic optimization process, molecular architectures were gene rated from a parent structure by virtual synthesis, and the best structure of a generation was selected as the parent for the subsequent TOPAS cycle. Similarity measures were used to define 'fitness', based on 2D-structural s imilarity or topological pharmacophore distance between the template molecu le and the variants. The concept of varying library 'diversity' during a de sign process was consequently implemented by using adaptive variant distrib utions. The efficiency of the design algorithm was demonstrated for the de novo construction of potential thrombin inhibitors mimicking peptide and no n-peptide template structures.