Determination of Multidirectional Pathways for Ligand Release from the Receptor: A New Approach Based on Differential Evolution

Steered molecular
dynamics (SMD) simulation is a powerful method
in computer-aided drug design as it can be used to access the relative
binding affinity with high precision but with low computational cost.
The success of SMD depends on the choice of the direction along which
the ligand is pulled from the receptor-binding site. In most simulations,
the unidirectional pathway was used, but in some cases, this choice
resulted in the ligand colliding with the complex surface of the exit
tunnel. To overcome this difficulty, several variants of SMD with
multidirectional pulling have been proposed, but they are not completely
devoid of disadvantages. Here, we have proposed to determine the direction
of pulling with a simple scoring function that minimizes the receptor–ligand
interaction, and an optimization algorithm called differential evolution
is used for energy minimization. The effectiveness of our protocol
was demonstrated by finding expulsion pathways of Huperzine A and
camphor from the binding site of Torpedo California acetylcholinesterase
and P450cam proteins, respectively, and comparing them with the previous
results obtained using memetic sampling and random acceleration molecular
dynamics. In addition, by applying this protocol to a set of ligands
bound with LSD1 (lysine specific demethylase 1), we obtained a much
higher correlation between the work of pulling force and experimental
data on the inhibition constant IC50 compared to that obtained using
the unidirectional approach based on minimal steric hindrance.