ES-Screen: A Novel Electrostatics-Driven Method for Drug Discovery Virtual Screening
Electrostatic interactions drive biomolecular interactions and associations. Computational modeling of electrostatics in biomolecular systems, such as protein-ligand, protein–protein, and protein-DNA, has provided atomistic insights into the binding process. In drug discovery, finding biologically p...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/14830 |
| _version_ | 1797463045943853056 |
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| author | Naiem T. Issa Stephen W. Byers Sivanesan Dakshanamurthy |
| author_facet | Naiem T. Issa Stephen W. Byers Sivanesan Dakshanamurthy |
| author_sort | Naiem T. Issa |
| collection | DOAJ |
| description | Electrostatic interactions drive biomolecular interactions and associations. Computational modeling of electrostatics in biomolecular systems, such as protein-ligand, protein–protein, and protein-DNA, has provided atomistic insights into the binding process. In drug discovery, finding biologically plausible ligand-protein target interactions is challenging as current virtual screening and adjuvant techniques such as docking methods do not provide optimal treatment of electrostatic interactions. This study describes a novel electrostatics-driven virtual screening method called ‘ES-Screen’ that performs well across diverse protein target systems. ES-Screen provides a unique treatment of electrostatic interaction energies independent of total electrostatic free energy, typically employed by current software. Importantly, ES-Screen uses initial ligand pose input obtained from a receptor-based pharmacophore, thus independent of molecular docking. ES-Screen integrates individual polar and nonpolar replacement energies, which are the energy costs of replacing the cognate ligand for a target with a query ligand from the screening. This uniquely optimizes thermodynamic stability in electrostatic and nonpolar interactions relative to an experimentally determined stable binding state. ES-Screen also integrates chemometrics through shape and other physicochemical properties to prioritize query ligands with the greatest physicochemical similarities to the cognate ligand. The applicability of ES-Screen is demonstrated with in vitro experiments by identifying novel targets for many drugs. The present version includes a combination of many other descriptor components that, in a future version, will be purely based on electrostatics. Therefore, ES-Screen is a first-in-class unique electrostatics-driven virtual screening method with a unique implementation of replacement electrostatic interaction energies with broad applicability in drug discovery. |
| first_indexed | 2024-03-09T17:46:07Z |
| format | Article |
| id | doaj.art-0ac123f28563472bb28ad1f89778b418 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:46:07Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0ac123f28563472bb28ad1f89778b4182023-11-24T11:08:41ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231483010.3390/ijms232314830ES-Screen: A Novel Electrostatics-Driven Method for Drug Discovery Virtual ScreeningNaiem T. Issa0Stephen W. Byers1Sivanesan Dakshanamurthy2Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USADepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USADepartment of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USAElectrostatic interactions drive biomolecular interactions and associations. Computational modeling of electrostatics in biomolecular systems, such as protein-ligand, protein–protein, and protein-DNA, has provided atomistic insights into the binding process. In drug discovery, finding biologically plausible ligand-protein target interactions is challenging as current virtual screening and adjuvant techniques such as docking methods do not provide optimal treatment of electrostatic interactions. This study describes a novel electrostatics-driven virtual screening method called ‘ES-Screen’ that performs well across diverse protein target systems. ES-Screen provides a unique treatment of electrostatic interaction energies independent of total electrostatic free energy, typically employed by current software. Importantly, ES-Screen uses initial ligand pose input obtained from a receptor-based pharmacophore, thus independent of molecular docking. ES-Screen integrates individual polar and nonpolar replacement energies, which are the energy costs of replacing the cognate ligand for a target with a query ligand from the screening. This uniquely optimizes thermodynamic stability in electrostatic and nonpolar interactions relative to an experimentally determined stable binding state. ES-Screen also integrates chemometrics through shape and other physicochemical properties to prioritize query ligands with the greatest physicochemical similarities to the cognate ligand. The applicability of ES-Screen is demonstrated with in vitro experiments by identifying novel targets for many drugs. The present version includes a combination of many other descriptor components that, in a future version, will be purely based on electrostatics. Therefore, ES-Screen is a first-in-class unique electrostatics-driven virtual screening method with a unique implementation of replacement electrostatic interaction energies with broad applicability in drug discovery.https://www.mdpi.com/1422-0067/23/23/14830electrostaticselectrostatic potentialelectrostatic energyfree energyvirtual screeninghit-to-lead identification |
| spellingShingle | Naiem T. Issa Stephen W. Byers Sivanesan Dakshanamurthy ES-Screen: A Novel Electrostatics-Driven Method for Drug Discovery Virtual Screening International Journal of Molecular Sciences electrostatics electrostatic potential electrostatic energy free energy virtual screening hit-to-lead identification |
| title | ES-Screen: A Novel Electrostatics-Driven Method for Drug Discovery Virtual Screening |
| title_full | ES-Screen: A Novel Electrostatics-Driven Method for Drug Discovery Virtual Screening |
| title_fullStr | ES-Screen: A Novel Electrostatics-Driven Method for Drug Discovery Virtual Screening |
| title_full_unstemmed | ES-Screen: A Novel Electrostatics-Driven Method for Drug Discovery Virtual Screening |
| title_short | ES-Screen: A Novel Electrostatics-Driven Method for Drug Discovery Virtual Screening |
| title_sort | es screen a novel electrostatics driven method for drug discovery virtual screening |
| topic | electrostatics electrostatic potential electrostatic energy free energy virtual screening hit-to-lead identification |
| url | https://www.mdpi.com/1422-0067/23/23/14830 |
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