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. 2023 Jun 5;62(23):e202303339.
doi: 10.1002/anie.202303339. Epub 2023 Mar 28.

Good Things Take Time: Tiwary-Seeliger Collaboration for Predictive Pharmacodynamics

MarkusA. Seeliger  1 , Pratyush Tiwary  2
Affiliations

Good Things Take Time: Tiwary-Seeliger Collaboration for Predictive Pharmacodynamics

MarkusA. Seeliger et al. Angew Chem Int Ed Engl. .

Abstract

This invited Team Profile was created by the Tiwary group, University of Maryland, College Park (USA) and the Seeliger group, Stony Brook University, New York (USA). They recently published an article on the previously made observation through in-cell screening that the blockbuster cancer drug Gleevec has the same binding affinity, yet different dissociation kinetics against wild-type and N368S-mutated Abl kinase. Through all-atom enhanced molecular dynamics simulations guided by statistical mechanics and information theory, they were able to explain the mechanistic basis of this perplexing observation. Their work has ramifications for how pharmaceutical drugs might experience kinetic resistance due to mutations. "Protein Flexibility and Dissociation Pathway Differentiation Can Explain Onset of Resistance Mutations in Kinases", M. Shekhar, Z. Smith, M. A. Seeliger, P. Tiwary, Angew. Chem. Int. Ed. 2022, e202200983; Angew. Chem. 2022, e202200983.

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References

    1. Lyczek Agatha, Berger Benedict-Tilman, Rangwala Aziz M., Paung YiTing, Tom Jessica, Philipose Hannah, Guo Jiaye et al. "Mutation in Abl kinase with altered drug-binding kinetics indicates a novel mechanism of imatinib resistance." Proceedings of the National Academy of Sciences 118, no. 46 (2021): e2111451118. 10.1073/pnas.2111451118 - DOI - PMC - PubMed
    1. Davoodi Shabnam, Daryaee Fereidoon, Chang Andrew, Walker Stephen G., and Tonge Peter J.. "Correlating Drug–Target Residence Time and Post-antibiotic Effect: Insight into Target Vulnerability." ACS infectious diseases 6, no. 4 (2020): 629–636. 10.1021/acsinfecdis.9b00484 - DOI - PMC - PubMed
    1. Shekhar Mrinal, Smith Zachary, Seeliger Markus A., and Tiwary Pratyush. "Protein flexibility and dissociation pathway differentiation can explain onset of resistance mutations in kinases." Angewandte Chemie International Edition 61, no. 28 (2022): e202200983. 10.1002/anie.202200983 - DOI - PMC - PubMed
    1. Shan Yibing, Kim Eric T., Eastwood Michael P., Dror Ron O., Seeliger Markus A., and Shaw David E.. "How does a drug molecule find its target binding site?." Journal of the American Chemical Society 133, no. 24 (2011): 9181–9183. 10.1021/ja202726y - DOI - PMC - PubMed
    1. Tiwary Pratyush, and Berne BJ. "Spectral gap optimization of order parameters for sampling complex molecular systems." Proceedings of the National Academy of Sciences 113, no. 11 (2016): 2839–2844. 10.1073/pnas.1600917113 - DOI - PMC - PubMed

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