NMR techniques for characterization of ligand binding: Utility for lead generation and optimization in drug discovery

Fragment based drug design represents a promising drug discovery paradigm complimentary to the traditional HTS based lead generation strategy. How to link fragment structures to increase compound affinity is remaining a challenge task in this paradigm. Hereby a novel deep generative model (AutoLinker) for linking fragments is developed with the potential for applying in the fragment-based lead generation scenario. The state-of-the-art transformer architecture was employed to learn the linker grammar and generate novel linker. Our results show that, given starting fragments and user customized linker constraints, our AutoLinker model can design abundant drug-like molecules fulfilling these constraints and its performance was superior to other reference models. Moreover, several examples were showcased that AutoLinker can be useful tools for carrying out drug design tasks such as fragment linking, lead optimization and scaffold hopping.

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The structure of SeviL, a GM1b/asialo-GM1 binding R-type lectin from the mussel Mytilisepta virgata

Scientific Reports ◽

10.1038/s41598-020-78926-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Kenichi Kamata ◽

Kenji Mizutani ◽

Katsuya Takahashi ◽

Roberta Marchetti ◽

Alba Silipo ◽

...

Keyword(s):

Immune System ◽

Sialic Acid ◽

Ligand Binding ◽

Steric Hindrance ◽

Sequence Similarity ◽

Binding Assays ◽

Subunit Interface ◽

Nmr Techniques ◽

And Control ◽

Asialo Gm1

AbstractSeviL is a recently isolated lectin found to bind to the linear saccharides of the ganglioside GM1b (Neu5Ac$$\alpha$$ α (2-3)Gal$$\beta$$ β (1-3)GalNAc$$\beta$$ β (1-4)Gal$$\beta$$ β (1-4)Glc) and its precursor, asialo-GM1 (Gal$$\beta$$ β (1-3)GalNAc$$\beta$$ β (1-4)Gal$$\beta$$ β (1-4)Glc). The crystal structures of recombinant SeviL have been determined in the presence and absence of ligand. The protein belongs to the $$\beta$$ β -trefoil family, but shows only weak sequence similarity to known structures. SeviL forms a dimer in solution, with one binding site per subunit, close to the subunit interface. Molecular details of glycan recognition by SeviL in solution were analysed by ligand- and protein-based NMR techniques as well as ligand binding assays. SeviL shows no interaction with GM1 due to steric hindrance with the sialic acid branch that is absent from GM1b. This unusual specificity makes SeviL of great interest for the detection and control of certain cancer cells, and cells of the immune system, that display asialo-GM1.

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Identification and Characterization of the Ligand Binding Subunit of a Kainic Acid Receptor Using Monoclonal Antibodies and Peptide Mapping

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)51632-x ◽

1989 ◽

Vol 264 (22) ◽

pp. 13329-13335

Author(s):

D R Hampson ◽

K D Wheaton ◽

C J Dechesne ◽

R J Wenthold

Keyword(s):

Monoclonal Antibodies ◽

Ligand Binding ◽

Kainic Acid ◽

Peptide Mapping ◽

Acid Receptor ◽

Identification And Characterization ◽

Binding Subunit

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Protein-ligand free energies of binding from full-protein DFT calculations: convergence and choice of exchange-correlation functional

Physical Chemistry Chemical Physics ◽

10.1039/d1cp00206f ◽

2021 ◽

Author(s):

Lennart Gundelach ◽

Christofer S Tautermann ◽

Thomas Fox ◽

Chris-Kriton Skylaris

Keyword(s):

Drug Discovery ◽

Ligand Binding ◽

Dft Calculations ◽

Quantum Mechanical ◽

Free Energies ◽

Ligand Interaction ◽

Exchange Correlation ◽

Ligand Free ◽

Protein Ligand Interaction ◽

Binding Free Energies

The accurate prediction of protein-ligand binding free energies with tractable computational methods has the potential to revolutionize drug discovery. Modeling the protein-ligand interaction at a quantum mechanical level, instead of...

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