QSAR analysis for pyrimidine and pyridine derivatives as RIPK2 (receptor interacting protein kinase 2) inhibitors

Abstract

Receptor-interacting protein kinase 2 (RIPK2) is a serine/threonine kinase that contains seven members in its family. RIPK2 inhibitors are used for the treatment of inflammatory bowel diseases (IBD), Crohn's disease and multiple sclerosis. It is also used to fight against various immune system disorders. RIPK2 inhibitors are found to be involved in different types of cancers like pancreatic, breast, SOC, colorectal cancer etc. Here, in the present work using the OECD guidelines, a dataset of 50 RIPK2 inhibitors having pyrimidine and pyridine heterocyclic moiety is used to develop robust QSAR models. The dataset is divided into training (38 compounds) and test set (12 compounds). All QSAR models are robust and fulfil the standard condition of internal and external validation parameters. The statistical parameters such as Q2 = 0.7701–0.8200, Rtrainingset2 = 0.8550–0.8843, Rtest2 = 0.8595–0.8924, CCCext = 0.8339–0.9030 etc are satisfied by these QSAR models in addition to other parameters. The 2nd QSAR model is selected as a leading model based on the numerical value of the MAEext of the test set. Molecular docking and molecular dynamics studies are performed with the most active compound. The leading model is used to design the five new compounds.