Docking Ligands into Flexible and Solvated Macromolecules. 7. Impact of Protein Flexibility and Water Molecules on Docking-Based Virtual Screening Accuracy

Abstract

The use of predictive computational methods in the drug discovery process is in a state of continual growth. Over the last two decades, an increasingly large number of docking tools have been developed to identify hits or optimize lead molecules through in-silico screening of chemical libraries to proteins. In recent years, the focus has been on implementing protein flexibility and water molecules. Our efforts led to the development of Fitted first reported in 2007 and further developed since then. In this study, we wished to evaluate the impact of protein flexibility and occurrence of water molecules on the accuracy of the Fitted docking program to discriminate active compounds from inactive compounds in virtual screening (VS) campaigns. For this purpose, a total of 171 proteins cocrystallized with small molecules representing 40 unique enzymes and receptors as well as sets of known ligands and decoys were selected from the Protein Data Bank (PDB) and the Directory of Useful Decoys (DUD), respectively. This study revealed that implementing displaceable crystallographic or computationally placed particle water molecules and protein flexibility can improve the enrichment in active compounds. In addition, an informed decision based on library diversity or research objectives (hit discovery vs lead optimization) on which implementation to use may lead to significant improvements.

Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description

“…Therrien et al reported that when screened compounds are similar one to each other, and they bind the same active site form, adopting a multiple receptor conformation (MRC) approach ameliorates the ranking of decoys. A much more significant improvement can be achieved when ligands are structurally different and/or are accommodated by diverse binding site conformations ( Figure 2) [24]. This is in line with what had been shown several years ago in protein kinases, where crystal structures and modeled receptor-ligand complexes were selected for MRC docking based on the chemical diversity of their bound ligands [62,63,66].…”

“…The "right' conformations should be able to provide the best results in terms of quantity and quality, where quantity corresponds to the percentage of active molecules identified in the early screening stage, and quality to the chemical diversity of these first ranked molecules. Both single-and multiple receptor conformation approaches [24] are significantly affected by the chosen binding site architecture, so that the key point is often represented by the capability of the conformational sampling to select the most representative states [145,190]. Some strategies were recently proposed to guide this conformational sampling.…”

“…Virtual procedures are also not affected by ligand purity, protein stability, or by the different samples and assays conditions [24]. However, VS suffers from a number of limitations stemming from the representation of the molecular system, the potential energy chosen to describe molecular interactions, and the inherent approximations.…”

Computational allosteric ligand binding site identification on Ras proteins

“…A number of excellent recent reviews have discussed the importance of incorporating structural flexibility to increase the success rate of CADD [100][101][102]. One of the most widely used methods to achieve this is MD simulation.…”

Role of computer-aided drug design in modern drug discovery

“…Even so, backbone displacement should also be considered since it can strengthen the accuracy of side chain orientations (Bolia et al 2014). Existing methods that incorporate partial protein flexibility include Glide, RosettaLigand (Davis and Baker 2009), FLIPDock (Zhao and Sanner 2007), and FITTED (Corbeil et al 2007(Corbeil et al , 2008Corbeil and Moitessier 2009;Englebienne and Moitessier 2009a, b;Pottel et al 2014;Therrien et al 2014). Solvation also plays a crucial role in ligand binding stability by mediating the interaction between receptor and ligand.…”