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

Mira Ahinko,Sami T Kurkinen,Sanna P Niinivehmas,Pekka A Postila,Olli T Pentikäinen

doi:10.3390/ijms20112779

Mira Ahinko, Sami T Kurkinen + Show 3 more

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https://doi.org/10.3390/ijms20112779

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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.

Highlights

Negative image-based (NIB) screening (Figure 1) is a rigid molecular docking methodology that combines the key strengths of both the structure- and ligand-based computer-aided drug discovery approaches [1]
The practical aspects of the negative image-based (NIB) and R-NiB methodologies are discussed below using a virtual screening or benchmarking example, i.e., the screening is performed using the directory of useful decoys (DUD) test set [18,19] and a celecoxib-bound cyclooxygenase-2 (COX-2) protein 3D structure (Figures 1 and 2; Protein Data Bank (PDB): 3LN1 [2])
This study described the practical steps and software settings to be used during the negative image-based (NIB; Figure 1) screening or the negative image-based rescoring (R-NiB; Figure 2)

Summary

Introduction

Negative image-based (NIB) screening (Figure 1) is a rigid molecular docking methodology that combines the key strengths of both the structure- and ligand-based computer-aided drug discovery approaches [1]. Sci. 2019, 20, x FOR PEER REVIEW (AUC) value of 0.50

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