Multimodal generative neural networks and molecular dynamics based identification of PDK1 PIF-pocket modulators

Vennila, K.N.; Elango, K. P.

doi:10.1039/d2me00051b

Cited by 5 publications

(1 citation statement)

References 33 publications

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“…This model encodes the voxelized pocket shape into ligand shapes, which are then decoded into valid molecular SMILES strings. Vennila and Elango [ 86 ] used the LiGANN to design potential pyruvate dehydrogenase kinase 1 modulators based on the defined allosteric site from 5 representative conformation states. The resulting top-ranking compounds exhibiting new scaffolds and high binding affinity were calculated by MD simulations.…”

Section: Allosteric Binding Modulator Discoverymentioning

confidence: 99%

A Structure-Based Allosteric Modulator Design Paradigm

Li,

Lan,

et al. 2023

Health Data Sci

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Importance: Allosteric drugs bound to topologically distal allosteric sites hold a substantial promise in modulating therapeutic targets deemed undruggable at their orthosteric sites. Traditionally, allosteric modulator discovery has predominantly relied on serendipitous high-throughput screening. Nevertheless, the landscape has undergone a transformative shift due to recent advancements in our understanding of allosteric modulation mechanisms, coupled with a significant increase in the accessibility of allosteric structural data. These factors have extensively promoted the development of various computational methodologies, especially for machine-learning approaches, to guide the rational design of structure-based allosteric modulators. Highlights: We here presented a comprehensive structure-based allosteric modulator design paradigm encompassing 3 critical stages: drug target acquisition, allosteric binding site, and modulator discovery. The recent advances in computational methods in each stage are encapsulated. Furthermore, we delve into analyzing the successes and obstacles encountered in the rational design of allosteric modulators. Conclusion: The structure-based allosteric modulator design paradigm holds immense potential for the rational design of allosteric modulators. We hope that this review would heighten awareness of the use of structure-based computational methodologies in advancing the field of allosteric drug discovery.

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Section: Allosteric Binding Modulator Discoverymentioning

confidence: 99%