Role of Molecular Dynamics and Related Methods in Drug Discovery

Marco De Vivo*, Matteo Masetti, Giovanni Bottegoni, Andrea Cavalli

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

361 Citations (Scopus)


Molecular dynamics (MD) and related methods are close to becoming routine computational tools for drug discovery. Their main advantage is in explicitly treating structural flexibility and entropic effects. This allows a more accurate estimate of the thermodynamics and kinetics associated with drug-target recognition and binding, as better algorithms and hardware architectures increase their use. Here, we review the theoretical background of MD and enhanced sampling methods, focusing on free-energy perturbation, metadynamics, steered MD, and other methods most consistently used to study drug-target binding. We discuss unbiased MD simulations that nowadays allow the observation of unsupervised ligand-target binding, assessing how these approaches help optimizing target affinity and drug residence time toward improved drug efficacy. Further issues discussed include allosteric modulation and the role of water molecules in ligand binding and optimization. We conclude by calling for more prospective studies to attest to these methods utility in discovering novel drug candidates.

Original languageEnglish
Pages (from-to)4035-4061
Number of pages27
JournalJournal of Medicinal Chemistry
Issue number9
Early online date25 Jan 2016
Publication statusPublished - 12 May 2016

Bibliographical note

ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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