Advances in NMR Methods to Identify Allosteric Sites and Allosteric Ligands

Abdelkarim, Hazem; Hitchinson, Ben; Banerjee, Avik; Gaponenko, Vadim

doi:10.1007/978-981-13-8719-7_8

Cited by 5 publications

(2 citation statements)

References 100 publications

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“…In recent years, the strategy of combining structural biology techniques (i.e., X-ray and cryo-EM) with computational methods (i.e., computational modeling and high-throughput virtual screening) has been used to determine the structures of the target proteins and to identify potential allosteric sites. , The allosteric sites have been used to facilitate the identification of novel inhibitors from large compound libraries. However, allosteric sites always vary in size, shape, and location in targeting proteins.…”

Section: Drug Design Targeting Slcsmentioning

confidence: 99%

Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

Tu,

Fu,

Zheng

et al. 2024

J. Chem. Inf. Model.

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Solute carrier transporters (SLCs) are a class of important transmembrane proteins that are involved in the transportation of diverse solute ions and small molecules into cells. There are approximately 450 SLCs within the human body, and more than a quarter of them are emerging as attractive therapeutic targets for multiple complex diseases, e.g., depression, cancer, and diabetes. However, only 44 unique transporters (∼9.8% of the SLC superfamily) with 3D structures and specific binding sites have been reported. To design innovative and effective drugs targeting diverse SLCs, there are a number of obstacles that need to be overcome. However, computational chemistry, including physics-based molecular modeling and machine learning-and deep learning-based artificial intelligence (AI), provides an alternative and complementary way to the classical drug discovery approach. Here, we present a comprehensive overview on recent advances and existing challenges of the computational techniques in structure-based drug design of SLCs from three main aspects: (i) characterizing multiple conformations of the proteins during the functional process of transportation, (ii) identifying druggability sites especially the cryptic allosteric ones on the transporters for substrates and drugs binding, and (iii) discovering diverse small molecules or synthetic protein binders targeting the binding sites. This work is expected to provide guidelines for a deep understanding of the structure and function of the SLC superfamily to facilitate rational design of novel modulators of the transporters with the aid of state-of-the-art computational chemistry technologies including artificial intelligence.

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Section: Drug Design Targeting Slcsmentioning

confidence: 99%

Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

Tu,

Fu,

Zheng

et al. 2024

J. Chem. Inf. Model.

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show abstract

“…Protein allostery, an effect caused by the coupling of distinct sites, plays an important role in protein function. , Through multiple coupled interactions, the perturbation at a remote site changes properties of the functional site (e.g., active site) and thus alters the function, such as catalysis or signal transduction . Nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for characterizing allosteric effects. − The atomic resolution of NMR spectroscopy provides information not only about the allosteric sites but also about the allosteric pathways. Meanwhile, researchers have made use of allosteric effects for enzyme engineering.…”

Section: Introductionmentioning

confidence: 99%

Protein Allostery Study in Cells Using NMR Spectroscopy

Chen,

Zhang,

Qin

et al. 2024

Anal. Chem.

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Protein allostery is commonly observed in vitro. But how protein allostery behaves in cells is unknown. In this work, a protein monomer−dimer equilibrium system was built with the allosteric effect on the binding characterized using NMR spectroscopy through mutations away from the dimer interface. A chemical shift linear fitting method was developed that enabled us to accurately determine the dissociation constant. A total of 28 allosteric mutations were prepared and grouped to negative allosteric, nonallosteric, and positive allosteric modulators. ∼ 50% of mutations displayed the allosteric-state changes when moving from a buffered solution into cells. For example, there were no positive allosteric modulators in the buffered solution but eight in cells. The change in protein allostery is correlated with the interactions between the protein and the cellular environment. These interactions presumably drive the surrounding macromolecules in cells to transiently bind to the monomer and dimer mutational sites and change the free energies of the two species differently which generate new allosteric effects. These surrounding macromolecules create a new protein allostery pathway that is only present in cells.

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Biophysical Approaches for the Characterization of Protein-Metabolite Interactions

Thalhammer

Bröker

2022

Methods in Molecular Biology

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Advances in NMR Methods to Identify Allosteric Sites and Allosteric Ligands

Cited by 5 publications

References 100 publications

Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

Protein Allostery Study in Cells Using NMR Spectroscopy

Biophysical Approaches for the Characterization of Protein-Metabolite Interactions

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