The role of water in ligand binding

Zsidó, Balázs Zoltán; Hetényi, Csaba

doi:10.1016/j.sbi.2020.08.002

Cited by 43 publications

(50 citation statements)

References 70 publications

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“…It is a real challenge to bring all these partners together into a hydrated complex structure due to the difficulties of correct positioning of interfacial water molecules. 25 …”

Section: Results and Discussionmentioning

confidence: 99%

“…Determination of water molecules mediating drug–target interactions is often missing or they are erroneously positioned due to inherent limitations of structure determination methods. 25 However, the COVID-19 pandemic showed that drug repositioning or design projects often fail due to such structural errors, resulting in misprediction of drug–target interactions. The present study showed that precise positioning of interfacial water molecules is essential for correct calculation of interaction of viral channels with amphipathic ligands of the AA type.…”

Section: Discussionmentioning

confidence: 99%

“…Their amino acid composition and water structure 25 are also key factors of ligand binding. The mediating role of water molecules was highlighted in the binding mechanism of AA derivatives to M2A.…”

Section: Introductionmentioning

confidence: 99%

“…As the full complex has not been solved at atomic resolution, we have to calculate the binding of the AA derivatives and the water structure from scratch, which is a challenging task for current methods. 25 To answer this challenge, we introduce a new protocol that will supply the water structure of the EC2 channel and also adopt docking and molecular dynamics steps to produce the representative binding modes of AA derivatives. The protocol will be tested on the old M2A target with available experimental complex structures as references and will be transferred to the new EC2 target.…”

Section: Introductionmentioning

confidence: 99%

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

Zsidó

Börzsei

Szél

et al. 2021

J. Chem. Inf. Model.

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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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“…It is a real challenge to bring all these partners together into a hydrated complex structure due to the difficulties of correct positioning of interfacial water molecules. 25 …”

Section: Results and Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Zsidó

Börzsei

Szél

et al. 2021

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, due to the extremely dynamic nature of water molecules, it remains challenging to experimentally characterize structural and thermodynamic solvation properties of the binding cavity in a protein. 22,23,25 Explicit solvent molecular dynamics (MD) simulations capture the motion of proteins in a solution environment, making it an ideal method for addressing the challenges in studying water in the buried regions of protein. 26 MD simulations have also been used extensively in studying detailed protein-ligand binding mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Intriguing Role of Water in Plant Hormone Perception

Zhao

Kleiman

Shukla

2021

Preprint

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Plant hormones are small molecules that regulate plant growth, development, and responses to biotic and abiotic stresses. Plant hormones are specifically recognized by the binding site of their receptors. In this work, we investigated the role of water displacement and reorganization at the binding site of plant receptors on the binding of eight classes of phytohormones (auxin, jasmonate, gibberellin, strigolactone, brassinosteroid, cytokinin, salicylic acid, and abscisic acid) using extensive molecular dynamics simulations and inhomogeneous solvation theory. Our findings demonstrated that displacement of water molecules by phytohormones contributes to free energy of binding via entropy gain and is associated with free energy barriers. Also, our results have shown that displacement of unfavorable water molecules in the binding site can be exploited in rational agrochemical design. Overall, this study uncov- ers the role of water molecules in plant hormone perception, which creates new avenues for agrochemical design to target plant growth and development.

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In silico investigation on structure–function relationship of members belonging to the human SLC52 transporter family

et al. 2022

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Riboflavin is an essential water-soluble vitamin that needs to be provided through the diet because of the conversion into flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), important cofactors in hundreds of flavoenzymes. The adsorption and distribution of riboflavin is mediated by transmembrane transporters of the SLC52 family, namely RFVT1-3, whose mutations are mainly associated with two diseases, MADD and the Brown-Vialetto-Van Laere syndrome. Interest in RFVTs as pharmacological targets has increased in the last few years due to their overexpression in several cancer cells, which can be exploited both by blocking the uptake of riboflavin into the cancerous cells, and by performing cancer targeted delivery of drugs with a high affinity for RFVTs. In this work, we propose three-dimensional structural models for all three human riboflavin transporters obtained by state-ofthe-art artificial intelligence-based methods, which were then further refined with molecular dynamics simulations. Furthermore, two of the most notable mutations concerning RFVT2 and RFVT3 (W31S and N21S, respectively) were investigated studying the interactions between the wild-type and mutated transporters with riboflavin.

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The role of water in ligand binding

Cited by 43 publications

References 70 publications

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

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

Intriguing Role of Water in Plant Hormone Perception

In silico investigation on structure–function relationship of members belonging to the human SLC52 transporter family

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