Simulation with quantum mechanics/molecular mechanics for drug discovery.
BACKGROUND
Biological macromolecules, such as proteins or nucleic acids, are (still) molecules and thus they follow the same chemical rules that any simple molecule follows, even if their size generally renders accurate studies unhelpful. However, in the context of drug discovery, a detailed analysis of ligand association is required for understanding or predicting their interactions and hybrid quantum mechanics/molecular mechanics (QM/MM) computations are relevant tools to help elucidate this process.


METHODS
In this review, the authors explore the use of QM/MM for drug discovery. After a brief description of the molecular mechanics (MM) technique, the authors describe the subtractive and additive techniques for QM/MM computations. The authors then present several application cases in topics involved in drug discovery.


CONCLUSIONS
QM/MM have been widely employed during the last decades to study chemical processes such as enzyme-inhibitor interactions. However, despite the enthusiasm around this area, plain MM simulations may be more meaningful than QM/MM. To obtain reliable results, the authors suggest fixing several keystone parameters according to the underlying chemistry of each studied system.
a Univ Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR CNRS 7086 , 15 rue J-A. de Baïf, Paris, France florent.barbault@univ-paris-diderot.fr.
Florent
F
Barbault
a Univ Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR CNRS 7086 , 15 rue J-A. de Baïf, Paris, France florent.barbault@univ-paris-diderot.fr.
François
F
Maurel
D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009696:Nucleic Acids / Q000737:chemistry; D011506:Proteins / Q000737:chemistry; D011789:Quantum Theory
D008024:Ligands; D009696:Nucleic Acids; D011506:Proteins
computer-aided drug design; drug discovery; hybrid method; molecular modeling; quantum chemistry; quantum mechanics/molecular mechanics