An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge

Jessica Lombino, Patrizia Diana, Ugo Perricone, Barbara Parrino, Girolamo Cirrincione, Stella Maria Cascioferro, Maria Rita Gulotta, Ugo Perricone, Maria Rita Gulotta, Jessica Lombino, Alessandro Padova

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


Molecular Dynamics (MD) has become increasingly popular due to the development of hardware and software solutionsand improvement in algorithms, that allowed researchers to scale up calculations in order to speed up them. MDsimulations are usually used to address protein folding issues or protein-ligand complex stability through energy profileanalysis over time. In recent years, the development of new tools able to deeply explore Potential Energy Surface (PES)allowed researchers to focus on the dynamic nature of binding recognition process and binding-induced proteinconformational change. Moreover, modern approaches have demonstrated to be effective and reliable in calculating somekinetic and thermodynamic parameters behind the host-guest recognition process. Starting from all of theseconsiderations, several efforts have been made in order to integrate MD within the virtual screening process in drugdiscovery. Knowledge retrieved from MD can be, in fact, exploited as a starting point to build pharmacophores or dockingconstraints in the early stage of the screening campaign as well as to define key features, in order to unravel hiddenbinding modes and help the optimisation of the molecular structure of a lead compound. Based on these outcomes,researchers are nowadays using MD as an invaluable tool to discover and target previously considered undruggablebinding sites, including protein-protein interactions and allosteric sites on protein surface. As a matter of fact, the use ofMD has been recognised as vital in the discovery of selective protein-protein interaction modulators. The use of a dynamicoverview on how the host-guest recognition occurs and of the relative conformational modifications induced, allowresearchers to optimise small molecules and small peptides capable to tightly interact within the cleft between the twoproteins.In this review we point to present the most recent applications of MD as integrated tool to be used in the rational designof small molecules or small peptides able to modulate undruggable targets, such as allosteric sites and protein-proteininteractions.
Original languageEnglish
Pages (from-to)920-936
Number of pages17
Publication statusPublished - 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry


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