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The Light and Dark Sides of Virtual Screening: What Is There to Know?
Open AccessArticle

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

1
Department of Biological and Environmental Science & Nanoscience Center, University of Jyvaskyla, P.O. Box 35, FI-40014 Jyvaskyla, Finland
2
Integrative Physiology and Pharmacy, Institute of Biomedicine, University of Turku, FI-20014 Turku, Finland
3
Aurlide Ltd., FI-21420 Lieto, Finland
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(11), 2779; https://doi.org/10.3390/ijms20112779
Received: 21 May 2019 / Revised: 3 June 2019 / Accepted: 4 June 2019 / Published: 6 June 2019
(This article belongs to the Special Issue Recent Advances in Virtual Screening)
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Abstract

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.
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Keywords: negative image-based (NIB) screening; negative image-based rescoring (R-NiB); molecular docking; rigid docking; docking rescoring; virtual screening; structure-based drug discovery; cyclooxygenase-2 (COX-2) negative image-based (NIB) screening; negative image-based rescoring (R-NiB); molecular docking; rigid docking; docking rescoring; virtual screening; structure-based drug discovery; cyclooxygenase-2 (COX-2)
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Ahinko, M.; Kurkinen, S.T.; Niinivehmas, S.P.; Pentikäinen, O.T.; Postila, P.A. A Practical Perspective: The Effect of Ligand Conformers on the Negative Image-Based Screening. Int. J. Mol. Sci. 2019, 20, 2779.

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