We acknowledge that this way of using biased sampling can also bias the configurations of molecules we make towards specific binding modes without adequately considering the space of all configurations. However, the goal here is to find molecules with stronger interaction and not so much to have a canonical ensemble of all possible binders in all possible binding poses. viii ) Fine-tuning the selection. It is normal to have energy oscillations in Metropolis Monte-Carlo. Therefore, directly allowing extremely poor binders as part of the Metropolis scheme is unfavorable. To encourage variability without affecting the interaction scores, we also perform heuristic fine-tuning.