Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?

Abstract

Molecular docking is a computational chemistry method which has become essential for the rational drug design process. In this context, it has had great impact as a successful tool for the study of ligand–receptor interaction modes, and for the exploration of large chemical datasets through virtual screening experiments. Despite their unquestionable merits, docking methods are not reliable for predicting binding energies due to the simple scoring functions they use. However, comparisons between two or three complexes using the predicted binding energies as a criterion are commonly found in the literature. In the present work we tested how wise is it to trust the docking energies when two complexes between a target protein and enantiomer pairs are compared. For this purpose, a ligand library composed by 141 enantiomeric pairs was used, including compounds with biological activities reported against seven protein targets. Docking results using the software Glide (considering extra precision (XP), standard precision (SP), and high-throughput virtual screening (HTVS) modes) and AutoDock Vina were compared with the reported biological activities using a classification scheme. Our test failed for all modes and targets, demonstrating that an accurate prediction when binding energies of enantiomers are compared using docking may be due to chance. We also compared pairs of compounds with different molecular weights and found the same results.

Comparing AutoDock and Vina in Ligand/Decoy Discrimination for Virtual Screening

“…This estimate, which in some cases is a prediction of the free energy of binding, must be able to discriminate between molecules that bind to the target and those that do not [23]. When looking at the two enantiomers, for example, it is still not possible to identify the most active form with most of the scoring functions used by the most common docking software [24].Even with all the significant improvements in computational power and docking software, considering all interactions that happen when a ligand binds to its target is an extremely challenging task. In order to be rigorous, the scoring functions would have to be much more complex, involve quantum calculations and, thus, these assays would turn out to be considerably expensive and time-consuming.…”

Acoplamiento Molecular: Avances Recientes y Retos

“…Therefore, the score of a given ligand does not tell much unless compared to a reference. In particular cases, the results may be ambiguous, i.e., symmetric ligands (Huang, Grinter & Zou, 2010) and enantiomer pairs (Ramírez & Caballero, 2016). Therefore, the problem is how to obtain quality poses from a scoring function.…”

Curcumin Analogues as the Inhibitors of TLR4 Pathway in Inflammation and Their Drug Like Potentialities: A Computer-based Study

“…Prime MM-GBSA RescoringAfter SP and XP ligand docking the ligands were then again subjected to Molecular mechanicsgeneralized born and surface area (MM-GBSA) rescoring with the help of Prime module of Maestro Schrödinger suite for further evaluation. This technique utilizes an implicit solvent which then assigns more accurate scoring function that then improves the overall free binding affinity score upon the reprocessing of the docked complex[66][68]. It combines OPLS molecular mechanics energies (E MM ), surface generalized born solvation model for polar solvation (G SGB ), and a nonpolar salvation term (G NP ) for total free energy (ΔG bind ) calculation.…”