Protein-Ligand Docking in the New Millennium – A Retrospective of 10 Years in the Field

Abstract

Protein-ligand docking is currently an important tool in drug discovery efforts and an active area of research that has been the subject of important developments over the last decade. These are well portrayed in the rising number of available protein-ligand docking software programs, increasing level of sophistication of its most recent applications, and growing number of users. While starting by summarizing the key concepts in protein-ligand docking, this article presents an analysis of the evolution of this important field of research over the past decade. Particular attention is given to the massive range of alternatives, in terms of protein-ligand docking software programs currently available. The emerging trends in this field are the subject of special attention, while old established docking alternatives are critically revisited. Current challenges in the field of protein-ligand docking such as the treatment of protein flexibility, the presence of structural water molecules and its effect in docking, and the entropy of binding are dissected and discussed, trying to anticipate the next years in the field.

Molecular Docking and Structure-Based Drug Design Strategies

“…These molecules are strongly bound to the receptor and observed across several crystallographic structures of a particular protein [107]. In approximately 65% of the crystallographic protein-ligand complexes, at least one water molecule is involved in ligand-receptor recognition [108].…”

“…Alternatively, structural water can be explicitly included in the docking experiments, allowing the formation of highly favorable hydrogen-bonding networks between the ligand and the target binding site. In this case, a variety of methods are available to evaluate which water molecules are strongly bound and, therefore, suitable for this purpose [107]. Among these strategies one can highlight free energy perturbation calculations using Monte Carlo statistical mechanics simulations, which estimate the binding free energy for a given water molecule, allowing the discrimination between displaceable and strongly-bound structural water [110].…”

Understanding the challenges of protein flexibility in drug design

“…In turn, this more realistic exploration of the binding event will also reflect the flexibility of the protein-ligand complex, probably predicting not only one "best" structure, but an ensemble of top-ranked alternative binding modes. Considering alternative binding modes will also have an impact on scoring methods, with respect to binding aspects that are often neglected, such as entropy [3], [5]. Indeed, more accurate binding energy estimations are a pressing issue for several docking applications [9], [149].…”

“…Indeed, more accurate binding energy estimations are a pressing issue for several docking applications [9], [149]. Finally, considering the diversity of methods and the difficulty to assess their performance, benchmarking efforts using stan-dard datasets are needed to highlight the advantages of each strategy [3], [150]. Future developments in the field will greatly benefit from the popularization of such practices.…”

Structure-Driven Pharmacology of Transient Receptor Potential Channel Vanilloid 1

“…This channel has become an attractive target for developing novel pain inhibitors because of its role in nociceptive and inflammatory responses. The structure of the TRPV1 channel has been resolved by cryo-EM (Cao et al, 2013b;Liao et al, 2013), and this work has provided most of the structural details for protein-ligand docking algorithms that rapidly evaluate the binding of thousands of compounds from virtual libraries (Sousa et al, 2013). However, the search of novel TRPV1 modulators can be a hard task because of the polymodal nature of this ion channel, which becomes a double-edged sword.…”