TY - JOUR
T1 - A Molecular Dynamics-Shared Pharmacophore Approach to Boost Early-Enrichment Virtual Screening: A Case Study on Peroxisome Proliferator-Activated Receptor α
AU - Tutone, Marco
AU - Perricone, Ugo
AU - Almerico, Anna Maria
AU - Perricone, Ugo
AU - Wieder, Marcus
AU - Seidel, Thomas
AU - Padova, Alessandro
AU - Langer, Thierry
PY - 2017
Y1 - 2017
N2 - Molecular dynamics (MD) simulations can be used, prior to virtual screening, to add flexibility to proteins and study them in a dynamic way. Furthermore, the use of multiple crystal structures of the same protein containing different co-crystallized ligands can help elucidate the role of the ligand on a protein′s active conformation, and then explore the most common interactions between small molecules and the receptor. In this work, we evaluated the contribution of the combined use of MD on crystal structures containing the same protein but different ligands to examine the crucial ligand-protein interactions within the complexes. The study was carried out on peroxisome proliferator-activated receptorα (PPARα). Findings derived from the dynamic analysis of interactions were then used as features for pharmacophore generation and constraints for generating the docking grid for use in virtual screening. We found that information derived from short multiple MD simulations using different molecules within the binding pocket of the target can improve the early enrichment of active ligands in the virtual screening process for this receptor. In the end we adopted a consensus scoring based on docking score and pharmacophore alignment to rank our dataset. Our results showed an improvement in virtual screening performance in early recognition when screening was performed with the Molecular dYnamics SHAred PharmacophorE (MYSHAPE) approach.
AB - Molecular dynamics (MD) simulations can be used, prior to virtual screening, to add flexibility to proteins and study them in a dynamic way. Furthermore, the use of multiple crystal structures of the same protein containing different co-crystallized ligands can help elucidate the role of the ligand on a protein′s active conformation, and then explore the most common interactions between small molecules and the receptor. In this work, we evaluated the contribution of the combined use of MD on crystal structures containing the same protein but different ligands to examine the crucial ligand-protein interactions within the complexes. The study was carried out on peroxisome proliferator-activated receptorα (PPARα). Findings derived from the dynamic analysis of interactions were then used as features for pharmacophore generation and constraints for generating the docking grid for use in virtual screening. We found that information derived from short multiple MD simulations using different molecules within the binding pocket of the target can improve the early enrichment of active ligands in the virtual screening process for this receptor. In the end we adopted a consensus scoring based on docking score and pharmacophore alignment to rank our dataset. Our results showed an improvement in virtual screening performance in early recognition when screening was performed with the Molecular dYnamics SHAred PharmacophorE (MYSHAPE) approach.
KW - Drug design; Dynamic pharmacophores; Molecular docking; PPARα; Virtual screening; Molecular Medicine; Pharmacology
KW - Toxicology and Pharmaceutics (all); Organic Chemistry
KW - Drug design; Dynamic pharmacophores; Molecular docking; PPARα; Virtual screening; Molecular Medicine; Pharmacology
KW - Toxicology and Pharmaceutics (all); Organic Chemistry
UR - http://hdl.handle.net/10447/240607
UR - http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201600526/full
M3 - Article
VL - 12
SP - 1399
EP - 1407
JO - Farmaco, Edizione Pratica
JF - Farmaco, Edizione Pratica
SN - 1860-7179
ER -