In silico design of novel indolinone-based anticancer agents and proposal of synthetic routes

Abstract

The RAF–MEK–ERK signaling pathway plays a central role in cancer development and progression and represents an important target for anticancer drug discovery. Simultaneous targeting of components of this pathway may therefore represent a promising strategy for cancer treatment. A quantitative structure-activity relationship (QSAR) model was developed using multiple linear regression (MLR). The QSAR model showed satisfactory predictive performance based on complementary internal and external validation metrics. The selected molecular descriptors were used to guide the structural modification of substituents, resulting in higher predicted activity. Accordingly, ten new molecules were designed through strategic substituent modifications. Synthetic routes for these compounds were also proposed based on reported literature procedures. Molecular docking, molecular dynamics (MD) simulations, and Petra, Osiris, and Molinspiration (POM) analyses supported the prioritization of Pred 9 and Pred 10 as computationally designed candidates for further investigation. In silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions indicated that Pred 9 and Pred 10 may exhibit favorable pharmacokinetic properties. Overall, the results support the consideration of these compounds for experimental synthesis and biological evaluation. However, Pred 9 and Pred 10 have not yet been synthesized or experimentally evaluated for MEK1 inhibition or anticancer activity.