Abstract:
:An evolutionary algorithm was developed for fragment-based de novo design of molecules (TOPAS, TOPology-Assigning System). This stochastic method aims at generating a novel molecular structure mimicking a template structure. A set of approximately 25,000 fragment structures serves as the building block supply, which were obtained by a straightforward fragmentation procedure applied to 36,000 known drugs. Eleven reaction schemes were implemented for both fragmentation and building block assembly. This combination of drug-derived building blocks and a restricted set of reaction schemes proved to be a key for the automatic development of novel, synthetically tractable structures. In a cyclic optimization process, molecular architectures were generated 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 similarity or topological pharmacophore distance between the template molecule and the variants. The concept of varying library 'diversity' during a design process was consequently implemented by using adaptive variant distributions. The efficiency of the design algorithm was demonstrated for the de novo construction of potential thrombin inhibitors mimicking peptide and non-peptide template structures.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Schneider G,Lee ML,Stahl M,Schneider Pdoi
10.1023/a:1008184403558subject
Has Abstractpub_date
2000-07-01 00:00:00pages
487-94issue
5eissn
0920-654Xissn
1573-4951journal_volume
14pub_type
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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