Another challenge for the construction of reliable SFs is the estimation of entropy. Entropy is one of the main driving forces of many chemical changes and a key component of the free energy of (bio)molecules. However, calculating the entropy of flexible, highly dynamic, molecules can be challenging, as the number of their possible conformations grows exponentially with their size. In addition to that, a large number of conformations can be of low energy and therefore thermally accessible. The number of conformations can be reduced by taking into account the inherent correlation between the multiple rotatable bonds and the terminal CH3 groups, as well as intramolecular interactions like π-π stackings and hydrogen bonds 39 . A fast and cost-effective way to calculate entropy (as has been recently proposed ) is pivotal, especially when the objective is to calculate the conformational entropy of a ligand bound to a protein so as to provide a better estimate of the free binding energies.