Structural dynamics and computer aided drug design targeting the COT kinase

Abstract

COT kinase is a target for drug discovery against cancer and autoimmune disorders. They are located downstream to the IKK2, unaffecting the NF – kappa B pathway. There is no such FDA approved drug against this protein and no extensive in-silico studies are being done till date. The structure is very unique as the P-loop is very flexible and a frameshift mutation exists in the αC helix. This study revolves around the structural dynamics study of COT Kinase in two forms- the apo and complex, both in unphosphorylated form and phosphorylated form. The phosphorylation is done on Threonine 290 residue. GaMD or Gaussian Accelerated Molecular Dynamics Simulation is done in triplicates for both the system. Further, the structural stability was studied for Phosphate binding loop(P-loop), Activation loop(A-loop), Catalytic loop(Cloop) and αC helix. Root Mean Square Fluctuation values and Root Mean Square Deviation values provided strong insights to the extensible flexibility of P-loop exclusively for phosphorylated and complex systems respectively. Virtual Screening is done to find out a potent inhibitor than the control molecule followed by ADMET analysis and simulation studies to check the protein stability when inhibitor binds to it. Also, the effect on structure when Mg is bound to it and Mn is bound to it, has been elucidated. It has been found that Manganese stabilizes the flexible P-loop.