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Determination of Ligand Binding Modes in Hydrated Viral Ion Channels to Foster Drug Design and Repositioning.
Zsidó, Balázs Zoltán; Börzsei, Rita; Szél, Viktor; Hetényi, Csaba.
  • Zsidó BZ; Pharmacoinformatics Unit, Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary.
  • Börzsei R; Pharmacoinformatics Unit, Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary.
  • Szél V; Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary.
  • Hetényi C; Pharmacoinformatics Unit, Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary.
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.
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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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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