Determination of Ligand Binding Modes in Hydrated Viral Ion Channels to Foster Drug Design and Repositioning.
J Chem Inf Model
; 61(8): 4011-4022, 2021 08 23.
Article
in English
| MEDLINE | ID: covidwho-1327180
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Drug Design
/
COVID-19
Type of study:
Prognostic study
Limits:
Humans
Language:
English
Journal:
J Chem Inf Model
Journal subject:
Medical Informatics
/
Chemistry
Year:
2021
Document Type:
Article
Affiliation country:
Acs.jcim.1c00488
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