Flexible loop regions play a critical role in the biological function of many proteins and have been shown to be involved in ligand binding. In the context of structure-based drug design, using or predicting an incorrect loop configuration can be detrimental to the study if the loop is capable of interacting with the ligand. Three protein systems, each with at least one flexible loop region in close proximity to the known binding site, were selected for loop prediction using the CorLps program; a six residue loop region from phosphoribosylglycinamide formyltransferase (GART), two nine residue loop regions from cytochrome P450 (CYP) 119, and an 11 residue loop region from enolase were selected for loop prediction. The results of this study indicate that the statistically based DFIRE scoring function implemented in the CorLps program did not accurately rank native-like predicted loop configurations in any protein system. In an attempt to improve the ranking of the native-like predicted loop configurations, the MM/GBSA and the optimized MM/GBSA-dsr scoring functions were used to re-rank the predicted loops with and without bound ligand. In general, single snapshot MM/GBSA scoring provided the best ranking of native-like loop configurations. Based on the scoring function analyses presented, the optimal ranking of native-like loop configurations is still a difficult challenge and the choice of the “best” scoring function appears to be system dependent. Proteins 2012; © 2011 Wiley Periodicals, Inc.