An improved relaxed complex scheme for receptor flexibility in computer-aided drug design

By R. Amaro, R. Baron, James Andrew McCammon. J. Comput. Aided Mol. Des., 2008

323 citations recorded by the source corpus.

The interactions among associating (macro)molecules are dynamic, which adds to the complexity of molecular recognition. While ligand flexibility is well accounted for in computational drug design, the effective inclusion of receptor flexibility remains an important challenge. The relaxed complex scheme (RCS) is a promising computational methodology that combines the advantages of docking algorithms with dynamic structural information provided by molecular dynamics (MD) simulations, therefore explicitly accounting for the flexibility of both the receptor and the docked ligands. Here, we briefly review the RCS and discuss new extensions and improvements of this methodology in the context of ligand binding to two example targets: kinetoplastid RNA editing ligase 1 and the W191G cavity mutant of cytochrome c peroxidase. The RCS improvements include its extension to virtual screening, more rigorous characterization of local and global binding effects, and methods to improve its computational efficiency by reducing the receptor ensemble to a representative set of configurations. The choice of receptor ensemble, its influence on the predictive power of RCS, and the current limitations for an accurate treatment of the solvent contributions are also briefly discussed. Finally, we outline potential methodological improvements that we anticipate will assist future development.

Subfields: Computational Theory and Mathematics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/24cdc1b3fac388a24bd168c57909aa4f31b6277d

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Citations in the corpus

Role of computer-aided drug design in modern drug discovery (2015, methodology): “(b) Ensemble - based approach exploits multiple receptor structures that are experimentally determined (X-ray crystallography or NMR) or computationally produced using molecular dynamics [relaxed complex scheme (RCS) (Amaro et al. 2008; Amaro and Li 2010)].”
Structure-based Systems Biology for Analyzing Off-target Binding (2011, background): “The modeling of protein flexibility requires computationally intensive molecular dynamic (MD) simulations, such as the relaxed complex schema [47,94,95].”
Bridging Molecular Docking to Molecular Dynamics in Exploring Ligand-Protein Recognition Process: An Overview (2018, background): “…particular, McCammon et al. developed the so-called Relaxed-Complex Scheme (RCS), consisting in docking mini-libraries of compounds with AutoDock (Morris et al., 1998) against a large ensemble of snapshots derived from unliganded protein MD trajectories (Lin et al., 2002, 2003; Amaro et al., 2008).”
Accounting for receptor flexibility and enhanced sampling methods in computer aided drug design (2013, methodology): “While one could just extract structures at equidistant time-points, it seems more logical to perform a clustering-type analysis and use a single representative of related structures (28) to cover a large conformational space without redundant structures.”
Computer-aided drug-discovery techniques that account for receptor flexibility. (2010, unknown): “Methods that probe global flexibility A number of global methodologies have been developed to overcome the limitations of methods that probe only local receptor flexibility [28 ,29].”
Molecular dynamics simulations and drug discovery (2011, methodology): “However, the alchemical techniques used to calculate free energies of binding are far more dependent on thorough conformational sampling than are RCS screens.”
Virtual screening strategies in drug discovery: a critical review. (2013, methodology): “The RCS uses an ensemble of low energy structures extracted from MD simulations to search ligand libraries via small molecule docking [92, 93].”
Virtual Screening with AutoDock: Theory and Practice (2010, methodology): “experimental structures (such as from NMR spectroscopy), or in the case of the ‘relaxed complex’ scheme, they may be a collection of conformations harvested from a molecular dynamics or a Monte Carlo simulation [36,37].”