Molecular dynamics simulations and novel drug discovery

ABSTRACT

Introduction: Molecular dynamics (MD) simulations can provide not only plentiful dynamical structural information on biomacromolecules but also a wealth of energetic information about protein and ligand interactions. Such information is very important to understanding the structure-function relationship of the target and the essence of protein–ligand interactions and to guiding the drug discovery and design process. Thus, MD simulations have been applied widely and successfully in each step of modern drug discovery.

Areas covered: In this review, the authors review the applications of MD simulations in novel drug discovery, including the pathogenic mechanisms of amyloidosis diseases, virtual screening and the interaction mechanisms between drugs and targets.

Expert opinion: MD simulations have been used widely in investigating the pathogenic mechanisms of diseases caused by protein misfolding, in virtual screening, and in investigating drug resistance mechanisms caused by mutations of the target. These issues are very difficult to solve by experimental methods alone. Thus, in the future, MD simulations will have wider application with the further improvement of computational capacity and the development of better sampling methods and more accurate force fields together with more efficient analysis methods.

KEYWORDS:

• Molecular dynamics simulation
• amyloidosis
• drug discovery
• virtual screening
• drug resistance

Article highlights

• MD simulations have a special advantage in exploring the conformational space of proteins and displaying the dynamic processes of structural changes.

• Amyloidosis is caused by the misfolding and aggregation of the related protein, and the pathogenic mechanism is still unclear due to the difficulty of experimental study.

• MD simulations can provide details of the misfolding and aggregation process and have been used widely to probe the pathogenic mechanism of amyloidosis.

• MD simulations can improve the enrichment factor of virtual screening by considering multiple target conformations during molecular docking and by giving a more accurate ranking of hit compounds in combination with binding free energy calculations.

• To improve the efficiency of lead optimization, MD simulations can be used to obtain accurate binding modes and binding abilities of compounds and to uncover the mechanism of drug resistance.

This box summarizes key points contained in the article.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [Grant No. 21375054 and No. 21675070] and the Fundamental Research Funds for the Central Universities [Grant No. lzujbky-2016-146 and No. lzujbky-2017-k24].