Structure and reaction based evaluation of synthetic accessibility

Abstract

De novo design systems provide powerful methods to suggest a set of novel structures with high estimated binding affinity. One deficiency of these methods is that some of the suggested structures could be synthesized only with great difficulty. We devised a scoring method that rapidly evaluates synthetic accessibility of structures based on structural complexity, similarity to available starting materials and assessment of strategic bonds where a structure can be decomposed to obtain simpler fragments. These individual components were combined to an overall score of synthetic accessibility by an additive scheme. The weights of the scoring function components were calculated by linear regression analysis based on accessibility scores derived from medicinal chemists. The calculated values for synthetic accessibility agree with the values proposed by chemists to an extent that compares well with how chemists agree with each other.

Second-generation de novo design: a view from a medicinal chemist perspective

“…Within the NovoBench project, the program system SYLVIA [9,10] was developed by Molecular Networks [18]. It allows for a rapid evaluation of the ease of synthesis of a given query compound.…”

“…Problems tackled are the creation of fragment spaces (Colibri), interactive design and browsing (FragView) as well as search problems like structure-based (FlexNovo [1]), ligand-based (Ftrees-FS [7]), and property-based (FragEnum [8]) design. All tools are combined with a novel approach to estimate synthetic accessibility of candidate compounds named SYLVIA [9,10]. These tools cannot be validated individually in this study.…”

“…Furthermore, assessing the synthetic feasibilities of the candidates had to be a focal point for a comprehensive and reliable novel de novo approach. Therefore, we used the program SYLVIA [9,10] as third component to assess the synthetic accessibility of all the candidate molecules. We provided an analysis on how accessible they were in comparison to their relative reference ligands and in comparison with actives that can be currently retrieved in a classical drug discovery database [11].…”

Multi-Parameter Optimization: Identifying High Quality Compounds with a Balance of Properties

“…One of the limitations of de novo design is the potential to propose unstable, unfeasible or synthetically intractable chemical structures. One of the advantages of the transformation rule based methods is that they tend to produce more acceptable structures, due to the fact that the transformations are based on historical precedents However, computational methods to estimate the synthetic tractability of compounds can help to discard irrelevant compounds generated by inappropriate mutations or combinations of structures [42].…”

Case Study 3: Fragment Hopping to Design Highly Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors

“…Although de novo design for lead discovery has been proposed since the 1980s, its success rate has been far behind than those of HTS and virtual screening. The main barriers to de novo design are (i) little considerations on the synthetic feasibility of newly constructed structures [23] and (ii) poor predictability of the used scoring functions [24]. On the basis of the concept that the structures of the biologically active compounds for a specific target are discontinuous points in the vast chemical space, scaffold hopping has been proposed to identify the compounds that have similar biological activities but totally different scaffolds [25][26][27], as described in the other chapters of this book.…”