Exploring the selective mechanism of inhibitors towards different subtypes of class I PI3K

Abstract The activation of the PI3K signaling pathway is closely related to the formation of various cancers. However, four subtypes of PI3K have a high degree of sequence homology, which is challenging to develop isomeric selective inhibitors. In this work, MD simulations and binding affinity calculations are combined to elucidate the interaction mechanism of different inhibitors towards PI3K subtypes. Key residues, hydrophobic interactions, and hydrogen bonds forming between the receptor and inhibitor are pointed out, which is critical to the understanding of the binding selectivity. This work can provide a theoretical reference for the design of more promising selective inhibitors.