Search for Novel Lead Inhibitors of Yeast Cytochrome bc1, from Drugbank and COCONUT.

Ozren Jović,Tomislav Šmuc

doi:10.3390/molecules26144323

Ozren Jović, Tomislav Šmuc

Open Access

https://doi.org/10.3390/molecules26144323

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Journal: Molecules (Basel, Switzerland)	Publication Date: Jul 16, 2021
Citations: 1	License type: CC BY 4.0

Affiliation: Rudjer Boskovic Institute

Abstract

In this work we introduce a novel filtering and molecular modeling pipeline based on a fingerprint and descriptor similarity procedure, coupled with molecular docking and molecular dynamics (MD), to select potential novel quoinone outside inhibitors (QoI) of cytochrome bc1 with the aim of determining the same or different chromophores to usual. The study was carried out using the yeast cytochrome bc1 complex with its docked ligand (stigmatellin), using all the fungicides from FRAC code C3 mode of action, 8617 Drugbank compounds and 401,624 COCONUT compounds. The introduced drug repurposing pipeline consists of compound similarity with C3 fungicides and molecular docking (MD) simulations with final QM/MM binding energy determination, while aiming for potential novel chromophores and perserving at least an amide (R1HN(C=O)R2) or ester functional group of almost all up to date C3 fungicides. 3D descriptors used for a similarity test were based on the 280 most stable Padel descriptors. Hit compounds that passed fingerprint and 3D descriptor similarity condition and had either an amide or an ester group were submitted to docking where they further had to satisfy both Chemscore fitness and specific conformation constraints. This rigorous selection resulted in a very limited number of candidates that were forwarded to MD simulations and QM/MM binding affinity estimations by the ORCA DFT program. In this final step, stringent criteria based on (a) sufficiently high frequency of H-bonds; (b) high interaction energy between protein and ligand through the whole MD trajectory; and (c) high enough QM/MM binding energy scores were applied to further filter candidate inhibitors. This elaborate search pipeline led finaly to four Drugbank synthetic lead compounds (DrugBank) and seven natural (COCONUT database) lead compounds—tentative new inhibitors of cytochrome bc1. These eleven lead compounds were additionally validated through a comparison of MM/PBSA free binding energy for new leads against those obtatined for 19 QoIs.

Highlights

Cytochrome bc1 is an important anaerobic respiratory chain component, where the electron transfer from substrate ubiquinol to cytochrome c is catalyzed with proton transfer across the membrane of bacteria or fungi [1]
In this work we examined the whole Drugbank (9680 compounds) and COCONUT Database (401,624 compounds) in order to find the subset that was most similar to the C3 group of fungicides, and to allow for new potential pharmacophore groups to be considered in this drug repurposing pipeline
Regarding the Drugbank repurposing pipeline, 9 hit compounds out of 20 meet the condition of higher highest scored conformation (HSC) Chemscore fitness than average fungicide HSC and two of them, DB09199 and DB04930, had different H-bonds to those already defined in specific H-bond (SHB), but were still considered for molecular dynamics (MD) simulations following the approach (1) due to the attained docking score higher than obtained for the top 1/3 quoinone outside inhibitors (QoI) (Table 1)

Summary

Introduction

Cytochrome bc is an important anaerobic respiratory chain component, where the electron transfer from substrate ubiquinol to cytochrome c is catalyzed with proton transfer across the membrane of bacteria or fungi [1]. That study was based on finding the strongest binding of the methoxyacrylate mode of action (MOA) antifungal inhibitors when optimizing the fragment attached to fungicide’s pharmacophore with protein side-chain residues in the Qo site. A recent study [5] considers fragment improvements of pyraclostrobin analogs, that contain methoxycarbamate pharmacophore as a MOA chemical group within the same site and target as methoxyacrylate inhibitors. Whether there are more confounding QoI-s within the known and approved drugs is unknown For this reason, drug repurposing of the Drugbank compounds for new lead proposals of Qo site inhibitors while searching for new MOA functional groups is still lacking in the literature to the best of our knowledge and should be carried out. We consider lead compounds of the newest open natural products database (COCONUT database) [9] to be a very interesting source as well, given that natural compounds have already provided an important role in the discovery of cytochrome bc inhibitors [10]

Methods

Results

Conclusion