Theoretical Study On The Interaction Of Inhibitors With SMO And G-quadruplex

The smoothened receptor(SMO)is a key transducer in the HH signaling pathway.GDC-0449 is the first marketed drug of SMO,which is mainly used for the treatment of advanced basal cell carcinoma.However,the D473H-SMO mutation confer resistance to the drug.Interestingly,the molecule LY2940680 and L4 designed by our collaborators still inhibit the activity of the D473H-SMO receptor in the experiment.In this paper,the binding mechanism of the above molecules bound to the WT-SMO and D473H-SMO was explored by theoretical calculations to deeply understand the resistance mechanisms caused by the D473 H mutation.In this work,the implicit membrane model was employed to calculate the solvation free energy.The calculated results indicate that the D473 H mutation can disrupt the hydrogen-bonding network in the binding pocket,which can weaken the binding of GDC;and the contribution of ARG400 and GLN477 to the binding is obviously reduced in the D473H-SMO compared to the wild system.But for the LY and L4,there are new hydrogen bond networks formed,which can stabilize their binding.This work provides a theoretical support to design more promising SMO inhibitors.The G-quadruplex is a special non-standard nucleic acid structure.Compared to proteins,the G-quadruplexs are more complicated,in which the Hoogsteen hydrogen bonds and monovalent metal ions are difficult to be accurately described by traditional molecular force fields,which seriously limits the computer-aided drug design work for the G-quadruplex.Based on the experimental data,this paper systematically investigated the reliability of two new molecular force fields(OL15 and bsc0)for Gquadruplex.The structural stability of the G-quadruplex complexes and the binding free energy between the G-quadruplex and fused ring compounds were explored based on the force fields.The results show that the bsc0 is better than the OL15 force field to stabilize the structure of the G-quadruplex.The calculation results of binding free energy indicate that the reliability of the two force fields still has a greater improvement.The related results provide an important reference for the development of new molecular force fields for G-quadruplexes.