De novo design methods

R. S. DeWitte and E. I. Shakhnovich, Smog de Novo design method based on simple,... 

Bohacek, R. S., McMartin, C. (1994) Multiple highly diverse structures complementary to enzyme binding sites results of extensive application of a de novo design method incorporating combinatorial growth. J Am Chem Soc 116, 5560-5571. 

While this version of the KTL successfully captured known kinase inhibitor series, the goal for our next-generation KTL would be to apply de novo design methods to incorporate novel chemotypes and to incorporate more nonclassical chemotypes that bind to a protein kinase beyond the typical ATP pocket. 

Automated de novo design methods seek to explore different molecular structures that could fit and bind to the site. They have general features in common ... 

DeWitte RS, Shakhnovich El (1996) SMoG de novo design method based on simple, fast, and accurate free energy estimates. 1. Methodology and supporting evidence. J Am Chem Soc 118 11733-11744... 

RS Bohacek, C McMartin (1994) Multiple Highly Diverse Structures Complementary to Enzyme Binding Sites Results of Extensive Application of a de Novo Design Method Incorporating Combinatorial Growth, J Am Chem Soc 116(13) 5560-5571... 

R S DeWitte, E I Shakhnovich (1996) SMoG de Novo Design Method Based on Simple, Fast, and Accurate Free Energy Estimates 1 Methodology and Supporting Evidence, J Am Chem Soc 118(47) 11733-11744... 

While de novo design methods can produce fully assembled structures, a chemist s expertise is often decisive for generation of novel leads that are synthetically accessible. Step-by-step fragment assembly under supervision of the human expert is implemented in SQUIRRELnovo, which can be used as an idea generator for medicinal chemistry. Fragments that are superposed with the query... 

Table 3 Novel ligands identified by de novo design methods...

Other successful homology models have been used in docking applications and have successfully resulted in the discovery of novel hits, include retinoic acid receptor (112). thyroid hormone receptor (113). CK2 kinase (114). SARS (severe acute respiratory syndrome) protease (115). CDK4 kinase (116). and SrC SH2 (117) for the application of de novo design methods (117). 

DeWitte. R.S. Ishchenko. A.V. Shakhnovich. E.I. SMoG. de Novo—Design method based on simple fast and aeeurate free energy estimates 2. Case studies in moleeular design. J. Am. Chem. Soc. 1997. 119. 4608-4617. 

More recently, another class of de novo design methods has been developed that uses medicinal chemistry transformation rules to generate new structures based on one or more input compounds. Due to the fact that these transformations are based on structural modifications made in practice during the course of optinmation projects, the resulting compounds are more likely to be synthetically accessible. Furthermore, these transformation methods have been combined with MPO methods, as described above, to guide the generation of new compoimd ideas based on the simultaneous optimization of multiple properties [41]. 

A process enabling rapid follow-up of compound ideas generated by de novo design methods has recently be demonstrated using microffuidic synthesis and screening [57]. This enables data on newly proposed compounds to be generated quickly and used to inform the predictions for future iterations of de novo design. 

Besnard et al. [58] described the apphcation of de novo design methods, using the existing drug donepazil as an initial compound, to identify leads with specific polypharmacological profiles and appropriate physicochemical and ADME properties for oral dosing and a target in the central nervous system. 

This study demonstrated how de novo design methods can be used to guide the discovery of high-quality lead compounds in the context of a fest follower project, starting with a known drug. 

The slippery slope How should we define a ligand design method For example, are fragment location techniques bona fide de novo design methods or simply a prerequisite for de novo design ... 

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