Molecular dynamics simulations and drug discovery

By Jacob D. Durrant, James Andrew McCammon. 2011

1,290 citations recorded by the source corpus.

This review discusses the many roles atomistic computer simulations of macromolecular (for example, protein) receptors and their associated small-molecule ligands can play in drug discovery, including the identification of cryptic or allosteric binding sites, the enhancement of traditional virtual-screening methodologies, and the direct prediction of small-molecule binding energies. The limitations of current simulation methodologies, including the high computational costs and approximations of molecular forces required, are also discussed. With constant improvements in both computer power and algorithm design, the future of computer-aided drug design is promising; molecular dynamics simulations are likely to play an increasingly important role.

Subfields: Computational Theory and Mathematics, Molecular Biology, Evaluation & Benchmarks

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Citations in the corpus

Molecular Docking and Structure-Based Drug Design Strategies (2015, background): “Usually the ligand stabilizes a subset of several possible conformations of the receptor, shifting the equilibrium toward the minimum energy structures [99].”
Enhanced Sampling Techniques in Molecular Dynamics Simulations of Biological Systems (2014, positive): “For example, one-microsecond simulation of a relatively small system (approximately 25,000 atoms) running on 24 processors requires months of computation to complete [11], and expensive petascale supercomputers must be employed to study larger systems [6,8,12–14].”
Protein structure-based drug design: from docking to molecular dynamics. (2018, background): “MD simulations of ligand binding and unbinding The application of MD to drug discovery projects is expanding, following the need for insights into binding, unbinding, and conformational change events at spatial and temporal resolution that is not available experimentally [10,68].”
Molecular Docking: Shifting Paradigms in Drug Discovery (2019, background): “In silico strategies, including molecular dynamics, have also been widely used to explore the conformational space of the investigated targets, ligands, and ligand-target complexes, and thus better describing the dynamic behavior of ligand-target complexes and refining the docking results [34,40,41]”
The future of molecular dynamics simulations in drug discovery (2011, background): “MD simulations seem to be good at identifying low-energy protein conformations that harbor cryptic drug binding sites [27].”
Molecular dynamics simulation for all (2018, positive): “How Can MD Contribute to Drug Discovery? Drug discovery provides a particularly interesting example of an area in which simulations can drive experiments (Borhani and Shaw, 2012; Durrant and McCammon, 2011).”
A Review on Applications of Computational Methods in Drug Screening and Design (2020, background): “According to different accuracy requirements, all-atom (AA), united-atom (UA), and coarse-grained (CG) MD simulations as well as explicit/implicit solvent models, which allow simulations of temporal and spatial scales, can be used to facilitate the drug discovery [25,26].”
GEOM: Energy-annotated molecular conformations for property prediction and molecular generation (2020, neutral): “(2) generates energy for overcoming torsional barriers.”
Ligand-biased ensemble receptor docking (LigBEnD): a hybrid ligand/receptor structure-based approach (2017, methodology): “On one end of the spectrum, fully flexible protein–ligand docking simulation using molecular dynamics methods have been proposed [19, 20].”
Molecular dynamics simulations and novel drug discovery (2018, background): “novel drug discovery, from structure–function relation studies of the targets to lead discovery and lead optimization [166].”
Bridging Molecular Docking to Molecular Dynamics in Exploring Ligand-Protein Recognition Process: An Overview (2018, background): “…MD simulations as source of target conformational profusion can be exploited to retrieve insights into cryptic pockets or allosteric binding sites (Durrant and McCammon, 2011), as reported by Schame et al., who identiﬁed an alternative binding site, named “trench,” close to the active site of the…”