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.