Cargando…

A Practical Perspective: The Effect of Ligand Conformers on the Negative Image-Based Screening

Negative image-based (NIB) screening is a rigid molecular docking methodology that can also be employed in docking rescoring. During the NIB screening, a negative image is generated based on the target protein’s ligand-binding cavity by inverting its shape and electrostatics. The resulting NIB model...

Descripción completa

Detalles Bibliográficos
Autores principales: Ahinko, Mira, Kurkinen, Sami T., Niinivehmas, Sanna P., Pentikäinen, Olli T., Postila, Pekka A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600450/
https://www.ncbi.nlm.nih.gov/pubmed/31174295
http://dx.doi.org/10.3390/ijms20112779
_version_ 1783431119036743680
author Ahinko, Mira
Kurkinen, Sami T.
Niinivehmas, Sanna P.
Pentikäinen, Olli T.
Postila, Pekka A.
author_facet Ahinko, Mira
Kurkinen, Sami T.
Niinivehmas, Sanna P.
Pentikäinen, Olli T.
Postila, Pekka A.
author_sort Ahinko, Mira
collection PubMed
description Negative image-based (NIB) screening is a rigid molecular docking methodology that can also be employed in docking rescoring. During the NIB screening, a negative image is generated based on the target protein’s ligand-binding cavity by inverting its shape and electrostatics. The resulting NIB model is a drug-like entity or pseudo-ligand that is compared directly against ligand 3D conformers, as is done with a template compound in the ligand-based screening. This cavity-based rigid docking has been demonstrated to work with genuine drug targets in both benchmark testing and drug candidate/lead discovery. Firstly, the study explores in-depth the applicability of different ligand 3D conformer generation software for acquiring the best NIB screening results using cyclooxygenase-2 (COX-2) as the example system. Secondly, the entire NIB workflow from the protein structure preparation, model build-up, and ligand conformer generation to the similarity comparison is performed for COX-2. Accordingly, hands-on instructions are provided on how to employ the NIB methodology from start to finish, both with the rigid docking and docking rescoring using noncommercial software. The practical aspects of the NIB methodology, especially the effect of ligand conformers, are discussed thoroughly, thus, making the methodology accessible for new users.
format Online
Article
Text
id pubmed-6600450
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-66004502019-07-16 A Practical Perspective: The Effect of Ligand Conformers on the Negative Image-Based Screening Ahinko, Mira Kurkinen, Sami T. Niinivehmas, Sanna P. Pentikäinen, Olli T. Postila, Pekka A. Int J Mol Sci Article Negative image-based (NIB) screening is a rigid molecular docking methodology that can also be employed in docking rescoring. During the NIB screening, a negative image is generated based on the target protein’s ligand-binding cavity by inverting its shape and electrostatics. The resulting NIB model is a drug-like entity or pseudo-ligand that is compared directly against ligand 3D conformers, as is done with a template compound in the ligand-based screening. This cavity-based rigid docking has been demonstrated to work with genuine drug targets in both benchmark testing and drug candidate/lead discovery. Firstly, the study explores in-depth the applicability of different ligand 3D conformer generation software for acquiring the best NIB screening results using cyclooxygenase-2 (COX-2) as the example system. Secondly, the entire NIB workflow from the protein structure preparation, model build-up, and ligand conformer generation to the similarity comparison is performed for COX-2. Accordingly, hands-on instructions are provided on how to employ the NIB methodology from start to finish, both with the rigid docking and docking rescoring using noncommercial software. The practical aspects of the NIB methodology, especially the effect of ligand conformers, are discussed thoroughly, thus, making the methodology accessible for new users. MDPI 2019-06-06 /pmc/articles/PMC6600450/ /pubmed/31174295 http://dx.doi.org/10.3390/ijms20112779 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ahinko, Mira
Kurkinen, Sami T.
Niinivehmas, Sanna P.
Pentikäinen, Olli T.
Postila, Pekka A.
A Practical Perspective: The Effect of Ligand Conformers on the Negative Image-Based Screening
title A Practical Perspective: The Effect of Ligand Conformers on the Negative Image-Based Screening
title_full A Practical Perspective: The Effect of Ligand Conformers on the Negative Image-Based Screening
title_fullStr A Practical Perspective: The Effect of Ligand Conformers on the Negative Image-Based Screening
title_full_unstemmed A Practical Perspective: The Effect of Ligand Conformers on the Negative Image-Based Screening
title_short A Practical Perspective: The Effect of Ligand Conformers on the Negative Image-Based Screening
title_sort practical perspective: the effect of ligand conformers on the negative image-based screening
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600450/
https://www.ncbi.nlm.nih.gov/pubmed/31174295
http://dx.doi.org/10.3390/ijms20112779
work_keys_str_mv AT ahinkomira apracticalperspectivetheeffectofligandconformersonthenegativeimagebasedscreening
AT kurkinensamit apracticalperspectivetheeffectofligandconformersonthenegativeimagebasedscreening
AT niinivehmassannap apracticalperspectivetheeffectofligandconformersonthenegativeimagebasedscreening
AT pentikainenollit apracticalperspectivetheeffectofligandconformersonthenegativeimagebasedscreening
AT postilapekkaa apracticalperspectivetheeffectofligandconformersonthenegativeimagebasedscreening
AT ahinkomira practicalperspectivetheeffectofligandconformersonthenegativeimagebasedscreening
AT kurkinensamit practicalperspectivetheeffectofligandconformersonthenegativeimagebasedscreening
AT niinivehmassannap practicalperspectivetheeffectofligandconformersonthenegativeimagebasedscreening
AT pentikainenollit practicalperspectivetheeffectofligandconformersonthenegativeimagebasedscreening
AT postilapekkaa practicalperspectivetheeffectofligandconformersonthenegativeimagebasedscreening