Nonpher: computational method for design of hard-to-synthesize structures

In cheminformatics, machine learning methods are typically used to classify chemical compounds into distinctive classes such as active/nonactive or toxic/nontoxic. To train a classifier, a training data set must consist of examples from both positive and negative classes. While a biological activity or toxicity can be experimentally measured, another important molecular property, a synthetic feasibility, is a more abstract feature that can’t be easily assessed. In the present paper, we introduce Nonpher, a computational method for the construction of a hard-to-synthesize virtual library. Nonpher is based on a molecular morphing algorithm in which new structures are iteratively generated by simple structural changes, such as the addition or removal of an atom or a bond. In Nonpher, molecular morphing was optimized so that it yields structures not overly complex, but just right hard-to-synthesize. Nonpher results were compared with SAscore and dense region (DR), other two methods for the generation of hard-to-synthesize compounds. Random forest classifier trained on Nonpher data achieves better results than models obtained using SAscore and DR data. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13321-017-0206-2) contains supplementary material, which is available to authorized users.