Determination of Ligand Binding Modes in Hydrated Viral Ion Channels to Foster Drug Design and Repositioning.

Viktor Szél,Csaba Hetényi,Balázs Zoltán Zsidó,Rita Börzsei

doi:10.1021/acs.jcim.1c00488

Viktor Szél, Csaba Hetényi + Show 2 more

Open Access

https://doi.org/10.1021/acs.jcim.1c00488

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Abstract

Target-based design and repositioning are mainstream strategies of drug discovery. Numerous drug design and repositioning projects have been launched to fight the ongoing COVID-19 pandemic. The resulting drug candidates have often failed due to the misprediction of their target-bound structures. The determination of water positions of such structures is particularly challenging due to the large number of possible drugs and the diversity of their hydration patterns. To answer this challenge and help correct predictions, we introduce a new protocol HydroDock, which can build hydrated drug–target complexes from scratch. HydroDock requires only the dry target and drug structures and produces their complexes with appropriately positioned water molecules. As a test application of the protocol, we built the structures of amantadine derivatives in complex with the influenza M2 transmembrane ion channel. The repositioning of amantadine derivatives from this influenza target to the SARS-CoV-2 envelope protein was also investigated. Excellent agreement was observed between experiments and the structures determined by HydroDock. The atomic resolution complex structures showed that water plays a similar role in the binding of amphipathic amantadine derivatives to transmembrane ion channels of both influenza A and SARS-CoV-2. While the hydrophobic regions of the channels capture the bulky hydrocarbon group of the ligand, the surrounding waters direct its orientation parallel with the axes of the channels via bridging interactions with the ionic ligand head. As HydroDock supplied otherwise undetermined structural details, it can be recommended to improve the reliability of future design and repositioning of antiviral drug candidates and many other ligands with an influence of water structure on their mechanism of action.

Highlights

The COVID-19 pandemic has generated a tsunami in targetbased drug design[1] and repositioning.[2]
We investigate the structural basis of repositioning of FDA-approved drugs amantadine (AA, Gocovri, Symmetrel) and its derivatives, rimantadine (RA, Flumadine) and spiroadamantyl amine (SA),[15−20] (Figure 1b) to the ion channel formed by the transmembrane domain of the SARS-CoV-2 envelope protein (EC2, Figure 1a) as a possible “new” target
An average of 3.7 ± 0.7 Å root-meansquare deviation (RMSD) was calculated between the docked and crystallographic ligand conformations with the latter ones used as references

Summary

Introduction

The COVID-19 pandemic has generated a tsunami in targetbased drug design[1] and repositioning.[2]. The clinical repositioning trials of a number of known drugs were launched in the past year[8−11] to test their applicability against the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). The structural dissimilarities between the active sites of proteases of HIV-1 and SARS-CoV-2 forecasted[12,13] the failure of recent repositioning trials[8,14] of HIV-1 protease inhibitors lopinavir and ritonavir to SARS-CoV-2. Such painful lessons highlight the necessity of a careful structure-based design and repositioning to reduce the number of failed clinical trials

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