Virtual Screening Using Pharmacophore Models Retrieved from Molecular Dynamic Simulations
Pharmacophore models are widely used for the identification of promising primary hits in compound large libraries. Recent studies have demonstrated that pharmacophores retrieved from protein-ligand molecular dynamic trajectories outperform pharmacophores retrieved from a single crystal complex struc...
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doaj-83d8a11761664808aced98f862d097142020-11-25T01:58:53ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-11-012023583410.3390/ijms20235834ijms20235834Virtual Screening Using Pharmacophore Models Retrieved from Molecular Dynamic SimulationsPavel Polishchuk0Alina Kutlushina1Dayana Bashirova2Olena Mokshyna3Timur Madzhidov4Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Hnevotinska 5, 77900 Olomouc, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Hnevotinska 5, 77900 Olomouc, Czech RepublicA.M. Butlerov Institute of Chemistry, Kazan Federal University, Kremlyovskaya Str. 18, 420008 Kazan, RussiaInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Hnevotinska 5, 77900 Olomouc, Czech RepublicA.M. Butlerov Institute of Chemistry, Kazan Federal University, Kremlyovskaya Str. 18, 420008 Kazan, RussiaPharmacophore models are widely used for the identification of promising primary hits in compound large libraries. Recent studies have demonstrated that pharmacophores retrieved from protein-ligand molecular dynamic trajectories outperform pharmacophores retrieved from a single crystal complex structure. However, the number of retrieved pharmacophores can be enormous, thus, making it computationally inefficient to use all of them for virtual screening. In this study, we proposed selection of distinct representative pharmacophores by the removal of pharmacophores with identical three-dimensional (3D) pharmacophore hashes. We also proposed a new conformer coverage approach in order to rank compounds using all representative pharmacophores. Our results for four cyclin-dependent kinase 2 (CDK2) complexes with different ligands demonstrated that the proposed selection and ranking approaches outperformed the previously described common hits approach. We also demonstrated that ranking, based on averaged predicted scores obtained from different complexes, can outperform ranking based on scores from an individual complex. All developments were implemented in open-source software pharmd.https://www.mdpi.com/1422-0067/20/23/5834pharmacophoremolecular dynamicsvirtual screening |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Pavel Polishchuk Alina Kutlushina Dayana Bashirova Olena Mokshyna Timur Madzhidov |
spellingShingle |
Pavel Polishchuk Alina Kutlushina Dayana Bashirova Olena Mokshyna Timur Madzhidov Virtual Screening Using Pharmacophore Models Retrieved from Molecular Dynamic Simulations International Journal of Molecular Sciences pharmacophore molecular dynamics virtual screening |
author_facet |
Pavel Polishchuk Alina Kutlushina Dayana Bashirova Olena Mokshyna Timur Madzhidov |
author_sort |
Pavel Polishchuk |
title |
Virtual Screening Using Pharmacophore Models Retrieved from Molecular Dynamic Simulations |
title_short |
Virtual Screening Using Pharmacophore Models Retrieved from Molecular Dynamic Simulations |
title_full |
Virtual Screening Using Pharmacophore Models Retrieved from Molecular Dynamic Simulations |
title_fullStr |
Virtual Screening Using Pharmacophore Models Retrieved from Molecular Dynamic Simulations |
title_full_unstemmed |
Virtual Screening Using Pharmacophore Models Retrieved from Molecular Dynamic Simulations |
title_sort |
virtual screening using pharmacophore models retrieved from molecular dynamic simulations |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2019-11-01 |
description |
Pharmacophore models are widely used for the identification of promising primary hits in compound large libraries. Recent studies have demonstrated that pharmacophores retrieved from protein-ligand molecular dynamic trajectories outperform pharmacophores retrieved from a single crystal complex structure. However, the number of retrieved pharmacophores can be enormous, thus, making it computationally inefficient to use all of them for virtual screening. In this study, we proposed selection of distinct representative pharmacophores by the removal of pharmacophores with identical three-dimensional (3D) pharmacophore hashes. We also proposed a new conformer coverage approach in order to rank compounds using all representative pharmacophores. Our results for four cyclin-dependent kinase 2 (CDK2) complexes with different ligands demonstrated that the proposed selection and ranking approaches outperformed the previously described common hits approach. We also demonstrated that ranking, based on averaged predicted scores obtained from different complexes, can outperform ranking based on scores from an individual complex. All developments were implemented in open-source software pharmd. |
topic |
pharmacophore molecular dynamics virtual screening |
url |
https://www.mdpi.com/1422-0067/20/23/5834 |
work_keys_str_mv |
AT pavelpolishchuk virtualscreeningusingpharmacophoremodelsretrievedfrommoleculardynamicsimulations AT alinakutlushina virtualscreeningusingpharmacophoremodelsretrievedfrommoleculardynamicsimulations AT dayanabashirova virtualscreeningusingpharmacophoremodelsretrievedfrommoleculardynamicsimulations AT olenamokshyna virtualscreeningusingpharmacophoremodelsretrievedfrommoleculardynamicsimulations AT timurmadzhidov virtualscreeningusingpharmacophoremodelsretrievedfrommoleculardynamicsimulations |
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