Abstract
Lead optimization is a crucial step in the drug discovery process, which aims to design potential drug candidates from biologically active hits. During lead optimization, active hits undergo modifications to improve their absorption, distribution, metabolism, excretion and toxicity (ADMET) profiles. Medicinal chemists face key questions regarding which compound(s) should be synthesized next and how to balance multiple ADMET properties. Reliable transformation rules from multiple experimental analyses are critical to improve this decision-making process. We developed OptADMET (https://cadd.nscc-tj.cn/deploy/optadmet/), an integrated web-based platform that provides chemical transformation rules for 32 ADMET properties and leverages prior experimental data for lead optimization. The multiproperty transformation rule database contains a total of 41,779 validated transformation rules generated from the analysis of 177,191 reliable experimental datasets. Additionally, 146,450 rules were generated by analyzing 239,194 molecular data predictions. OptADMET provides the ADMET profiles of all optimized molecules from the queried molecule and enables the prediction of desirable substructure transformations and subsequent validation of drug candidates. OptADMET is based on matched molecular pairs analysis derived from synthetic chemistry, thus providing improved practicality over other methods. OptADMET is designed for use by both experimental and computational scientists.
Key points
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OptADMET is an integrated web-based tool that uses the data-driven chemical transformation rules for 32 absorption, distribution, metabolism, excretion and toxicity properties. The database contains 41,779 validated transformation rules generated from the analysis of 177,191 reliable experimental datasets.
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OptADMET provides the absorption, distribution, metabolism, excretion, and toxicity profiles of optimized molecules from a queried lead candidate and informs on the subsequent validation of drug candidates.
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Data availability
The output files can be downloaded from https://cadd.nscc-tj.cn/deploy/optadmet/.
Code availability
The software is available from https://cadd.nscc-tj.cn/deploy/optadmet/. Code for deployment of OptADMET is in the GitHub repository (https://github.com/antwiser/OptADMET)
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Acknowledgements
We thank the user community for using OptADMET and providing us with valuable suggestions regarding further improvement of this tool. We also acknowledge H. Xu, and the High-Performance Computing Center of Central South University for support. The study was approved by the university’s review board. This work was supported by National Key Research and Development Program of China (2021YFF1201400), National Natural Science Foundation of China (22173118, 22220102001), Hunan Provincial Science Fund for Distinguished Young Scholars (2021JJ10068), the science and technology innovation Program of Hunan Province (2021RC4011), the Natural Science Foundation of Hunan Province (2022JJ80104), and the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (2020B1212030006, Guangdong-Hong Kong-Macau Joint Lab).
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T.H. and D.C. conceived and supervised the project. J.Y. and Z.Y. designed and developed the web server. S.S., L.F. and J.Y. wrote the manuscript. P.N., A.L., C.W., Y.D., C.H. and X.Z. co-supervised the project and helped with troubleshooting. All authors reviewed and approved the manuscript.
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Key references using this protocol
Xiong, G. et al. Nucleic Acids Res. 49, W5–W14 (2021): https://doi.org/10.1093/nar/gkab255
Yang, Z.-Y. et al. J. Cheminform. 13, 86 (2021): https://doi.org/10.1186/s13321-021-00564-6
Fu, L. et al. Brief. Bioinform. 22, bbaa374 (2021): https://doi.org/10.1093/bib/bbaa374
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Supplementary Figs. 1–5 and Tables 1–5.
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Yi, J., Shi, S., Fu, L. et al. OptADMET: a web-based tool for substructure modifications to improve ADMET properties of lead compounds. Nat Protoc 19, 1105–1121 (2024). https://doi.org/10.1038/s41596-023-00942-4
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DOI: https://doi.org/10.1038/s41596-023-00942-4
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