Elaborate ligand-based modeling and subsequent synthetic exploration unveil new nanomolar Ca2+/calmodulin-dependent protein kinase II inhibitory leads

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) has been recently implicated in cardiovascular diseases and hypertension prompting several attempts to discover and optimize new CaMKIIδ inhibitors. Towards this end we explored the pharmacophoric space of 88 CaMKIIδ inhibitors using nine diverse sets of inhibitors to identify high quality pharmacophores. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing self-consistent quantitative structure-activity relationship (QSAR) of optimal predictive potential (r(72)(2)=0.70, F=18.19, r(LOO)(2)=0.71, r(PRESS)(2) against 16 external test inhibitors=0.60). Three orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least three binding modes accessible to ligands within CaMKIIδ binding pocket. Receiver operating characteristic (ROC) curves analysis established the validity of QSAR-selected pharmacophores. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute (NCI) list of compounds. In silico screening identified nanomolar and low micromolar inhibitors. The most potent hits exhibited IC(50) values of 20 and 82nM. The best pharmacophoric model (Hypo8/31) was employed to guide the synthesis of novel triazine-based CaMKIIδ inhibitors, of which the most potent illustrated an IC(50) value of 154nM against CaMKIIδ.