FlexNovo is a new molecular design program based on the FlexX-technology. It facilitates a fragment-based approach to de novo design in the context of the 3D-structure of the target.
- Fragment spaces consist of sets of molecular fragments that have specific 'link atoms' as open valences. Different 'link types' represent different chemical environments. A set of rules determines which link types are compatible (i.e. can be connected). Fragment spaces can be focused libraries derived from known binders or general fragment collections with link-rules. A space with only 16 000 fragments spans easily a chemical space of about 1018 virtual compounds of reasonable size, thus covering, a considerable part of the 'chemical universe'.
- The FlexNovo algorithm is based on the incremental construction procedure as implemented in FlexX. In a first step FlexNovo places all available fragments. It takes the best scoring fragments entering the following steps during which compatible fragments are successively added to the so far obtained set of placements. All available scoring functions known from FlexX can be used for ranking the (intermediate) results. Additionally, FlexNovo considers a multitude of physicochemical property, geometry and diversity filter criteria. For the initial placement step, it also evaluates the compliance with pharmacophore-type constraints as known from FlexX-Pharm.
- In a first feasibility study, FlexNovo has been used to design potential inhibitors for four targets of pharmaceutical interest: dihydrofolate reductase, cyclin-dependant kinase 2, cyclooxygenase-2 and estrogen receptor. For each of these targets solution sets were generated that consist of up to 50 de novo molecules. All of the sets contained chemically reasonable structures that have similar structural motifs when compared to known active structures. The solutions also mimic the corresponding binding orientations. Additionally, the distribution of a number of physicochemical properties within such a set is reasonable and similar compared to distributions obtained from sets of known active structures.
FlexNovo is meant to be an integrated and user-customizable idea-generating system. It may help in suggesting new structural motifs, designing libraries of lead-prototypes and in proposing novel scaffolds as well as alternative binding modes for a target protein. The software can even be more powerful if there is expert knowledge integrated, for example, considering key interactions with the target, specific chemical motifs or certain physicochemical properties.
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| features |
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Docking of large fragment spaces and focused fragment libraries |
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De novo design of compounds or libraries by searching in large fragment spaces |
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Filtering based on physicochemical and geometric properties and solution list diversity criteria |
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Identification of novel scaffolds, lead prototypes and alternative binding modes for a given target |
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| complementary software |
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Fragment spaces as input for FlexNovo can be generated by CoLibri, BioSolveITs library design toolkit. Additionally, pre-defined fragment spaces derived from vendor compound collections can be obtained from BioSolveIT upon request. For similarity-based de novo design FTrees-FS is the method of choice.
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| status & availability |
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FlexNovo is under ongoing and further development at the Center for Bioinformatics (ZBH) of the University of Hamburg and available as a prototype only. Currently, three pharma and biotech companies make use of its functionality. If you are interested in beta-testing this software, please request an extended evaluation license here. The Software is available for the Linux x86 (32 and 64bit) platform from the download page.
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| contact |
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If you need more (technical) information concerning FlexNovo, please refer to the developers' web-page at the Center for Bioinformatics (ZBH) of the University of Hamburg. You may also pose your question in the support center or send us your message or suggestions to FlexNovo@BioSolveIT.de.
Your feedback is very valuable and enables us to further develop and improve our software!
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m this link leads back to mother tool FlexX |
