The importance of having enough replicas when conducting MD simulations has been disclosed in the literature 61 and is also highlighted in recent editorials 62, . This requirement has also been exemplified by our simulations, where we observed some instability of the ligands in the binding pocket in 2/20 and 1/20 simulations of GDC-6036 and LY3537982, respectively. Notably, the ligands in our simulations were already optimized, high-affinity covalent inhibitors. This is emphasizing the fact that the requirements for sufficient replicas cannot be overlooked.