Challenges and current status of computational methods for docking small molecules to nucleic acids

Abstract

Since the development of the first docking program in 1982, their use in in silico screening for potentially bioactive molecule discovery has become a common strategy in academia and pharmaceutical industry. Up until recently, their use has largely focused on drugs binding to proteins. However, with the relatively recent discovery of promising drug targets in nucleic acids, including RNA riboswitches, DNA G-quadruplexes, and extended repeats in RNA, there has been a greater interest in developing drugs for nucleic acids. However, due to the major biochemical and physical differences in charges, binding pockets, and solvation, existing docking programs, developed for proteins, face difficulties when adopted directly for nucleic acids. In this review, we cover the current field of in silico docking to nucleic acids, available programs, as well as challenges faced in the field.

How ‘Protein-Docking’ Translates into the New Emerging Field of Docking Small Molecules to Nucleic Acids?

“…Finally, we want to rationalize the advances and performances of docking programs applied to nucleic acids along the history, which refers to works retrieved from the literature [57,[71][72][73][74]. However, we have to warn the reader that literature on docking programs applied to nucleic acids is less abundant compared to protein docking and because of the small data set used, sometimes, an appropriate statistical comparison results in being difficult.…”

Augmented base pairing networks encode RNA-small molecule binding preferences

“…affinity) is directly computed. Affinity scores are usually computed using docking techniques [31], using various pose-finding algorithms and scoring schemes have been proposed, including some specialized for RNA [21,38,37,27]. Although potentially more accurate than ligand-based methods, structure-based approaches are severely limited by the computational cost of docking and virtual screening.…”

“…In particular, the number of candidate ligands largely exceeds the number of molecules that could possibly be processed (10 8 vs 10 24 possible chemical compounds [12]). In addition, the modelling of interactions between RNAs and small molecules still needs improvement to reach the performance of protein-ligand docking [27,44].…”

“…1). This paradigm distinguishes RNA from protein-ligand interactions where surface cavity topologies drive binding preferences [27]. Indeed, graphical representations of RNA base pairing networks have been developed in various tools [41,42,35,7] for their ability to capture RNA-specific interactions in a scalable and interpretable manner.…”

Integrative Modelling of Biomolecular Complexes: From Small to Large

“…A detailed overview of the challenges of the various types of docking depending on the nature of the interacting biomolecules such as protein-protein 1,43 , protein-nucleic acid [44][45][46] , proteinsmall molecule 47,48 and protein-peptide 49 is beyond the scope of this mini review as are the intricate details of the algorithms used by various docking programs to achieve good sampling and scoring performance. The latter is something that has been continuously evaluated over a period spanning almost 20 years in CAPRI (Critical Assessment of Protein Interactions) 50 the blind docking experiment [51][52][53][54][55] .…”