Scoring synthetic feasibility: A very different problem
Presentation held at:
237th ACS National Meeting; CINF 73
March 2009, Salt Lake City, UT, USA
March 2009, Salt Lake City, UT, USA
ABSTRACT
A huge amount of effort has gone into the problem of predicting the binding affinity of given poses of hypothetical ligands docked to protein binding sites. However, if these hypothetical ligands have been produced by de novo design, an equally important consideration is whether they are synthetically accessible. Over the past decade, we have attempted to address this problem in a variety of ways. The CAESA program combines an empirical approach to molecular complexity with a relatively rapid retrosynthetic analysis to find starting materials, the hypothesis being that complexity contained within readily available starting materials is apparent rather than true complexity. An alternative approach, incorporated into the SPROUT program, analyses structural complexity by comparing substitution patterns of ligand structures with those found in known drugs and databases of commercially available starting materials. The relative merits of these approaches will be discussed.
A huge amount of effort has gone into the problem of predicting the binding affinity of given poses of hypothetical ligands docked to protein binding sites. However, if these hypothetical ligands have been produced by de novo design, an equally important consideration is whether they are synthetically accessible. Over the past decade, we have attempted to address this problem in a variety of ways. The CAESA program combines an empirical approach to molecular complexity with a relatively rapid retrosynthetic analysis to find starting materials, the hypothesis being that complexity contained within readily available starting materials is apparent rather than true complexity. An alternative approach, incorporated into the SPROUT program, analyses structural complexity by comparing substitution patterns of ligand structures with those found in known drugs and databases of commercially available starting materials. The relative merits of these approaches will be discussed.
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