In silico discovery of small molecules for efficient stem cell differentiation into definitive endoderm
Gherman Novakovsky, Shugo Sasaki, Oriol Fornés, Meltem E. Omur, Helen Huang, Carmen Bayly, Dahai Zhang, Nathaniel C. Lim, Artem Cherkasov, Paul Pavlidis, Sara Mostafavi, Francis C. Lynn, Wyeth W. Wasserman
Abstract
Improving methods for human embryonic stem cell differentiation represents a challenge in modern regenerative medicine research. Using drug repurposing approaches, we discover small molecules that regulate the formation of definitive endoderm. Among them are inhibitors of known processes involved in endoderm differentiation (mTOR, PI3K, and JNK pathways) and a new compound, with an unknown mechanism of action, capable of inducing endoderm formation in the absence of growth factors in the media. Optimization of the classical protocol by inclusion of this compound achieves the same differentiation efficiency with a 90% cost reduction. The presented in silico procedure for candidate molecule selection has broad potential for improving stem cell differentiation protocols.