In the case of the EQ method, ensemble size and/or replica length could be increased to bring uncertainties under the threshold required. We suggest first increasing the ensemble size as uncertainty is better captured by this. In the case of the NEQ method, there is an additional requirement of ensuring overlap and also additional parameters to adjust. Therefore, it is tricky to choose the most efficient order in which to adjust these parameters to ensure reliability. Fortunately, our analyses allow us to provide useful insights in this regard. Given that the distance values are the most sensitive to the number of transitions per replica, we propose to first of all increase its value in a stepwise manner up to maximum 100. This should already filter out a large fraction of the shortlisted compounds. Thereafter, we recommend increasing the transition length up to 2 ns. Finally, for the remaining compounds, ensemble size (followed by replica length) should be increased. The suggested maximum values of 100 transitions per replica (leading to 1000 transitions overall using ensemble size 10) and 2 ns long transitions are provided as guidelines for users to decide when to start adjusting the next parameter in order. However, there may be some cases where one would need to breach even these maximum values depending on system requirements and user preferences.