Combination of consensus and ensemble docking strategies for the discovery of human dihydroorotate dehydrogenase inhibitors

Garri Chilingaryan,Hovakim Zakaryan,Arsen Sargsyan,Narek Abelyan,Karen Nazaryan,Andre Serobian

doi:10.1038/s41598-021-91069-7

Abstract

The inconsistencies in the performance of the virtual screening (VS) process, depending on the used software and structural conformation of the protein, is a challenging issue in the drug design and discovery field. Varying performance, especially in terms of early recognition of the potential hit compounds, negatively affects the whole process and leads to unnecessary waste of the time and resources. Appropriate application of the ensemble docking and consensus-scoring approaches can significantly increase reliability of the VS results. Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the pyrimidine biosynthesis pathway. It is considered as a valuable therapeutic target in cancer, autoimmune and viral diseases. Based on the conducted benchmark study and analysis of the effect of different combinations of the applied methods and approaches, here we suggested a structure-based virtual screening (SBVS) workflow that can be used to increase the reliability of VS.

Highlights

The inconsistencies in the performance of the virtual screening (VS) process, depending on the used software and structural conformation of the protein, is a challenging issue in the drug design and discovery field
In the context of the ongoing pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), referred to as coronavirus disease 2019 (COVID-19), hDHODH inhibitors are considered as potential host targeting antiviral treatment of COVID-197–9
As a result of clusterization based on RMS deviation of the interacting amino acid residues of the ubiquinone binding site of hDHODH, four clusters were selected (Fig. 2B)

Summary

Introduction

The inconsistencies in the performance of the virtual screening (VS) process, depending on the used software and structural conformation of the protein, is a challenging issue in the drug design and discovery field. Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the pyrimidine biosynthesis pathway It is considered as a valuable therapeutic target in cancer, autoimmune and viral diseases. A number of open-source academic and commercial molecular docking software packages show quite varied performances depending on protein family and on crystal structure of the p rotein[14,15,16,17,18,19,20,21] In this context, the traditional approach in using a single software and structural conformation to screen a large database of molecules may lead to the questionable results. While we developed and tested SBVS workflow for hDHODH, we tested and discussed its general application and efficiency

Methods

Results

Conclusion