Frontiers of Medicine

, Volume 13, Issue 2, pp 277–284 | Cite as

In silico design of novel proton-pump inhibitors with reduced adverse effects

  • Xiaoyi Li
  • Hong Kang
  • Wensheng Liu
  • Sarita Singhal
  • Na Jiao
  • Yong Wang
  • Lixin ZhuEmail author
  • Ruixin ZhuEmail author
Research Article


The development of new proton-pump inhibitors (PPIs) with less adverse effects by lowering the pKa values of nitrogen atoms in pyrimidine rings has been previously suggested by our group. In this work, we proposed that new PPIs should have the following features: (1) number of ring II = number of ring I + 1; (2) preferably five, six, or seven-membered heteroatomic ring for stability; and (3) 1 < pKa1 < 4. Six molecular scaffolds based on the aforementioned criteria were constructed, and R groups were extracted from compounds in extensive data sources. A virtual molecule dataset was established, and the pKa values of specific atoms on the molecules in the dataset were calculated to select the molecules with required pKa values. Drug-likeness screening was further conducted to obtain the candidates that significantly reduced the adverse effects of long-term PPI use. This study provided insights and tools for designing targeted molecules in silico that are suitable for practical applications.


proton-pump inhibitor adverse effect pharmacological mechanism toxicological mechanism pKa calculation 


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This work was supported by National Natural Science Foundation of China (Nos. 31200986 and 41530105) (to RZ), Natural Science Foundation, the Shanghai Committee of Science and Technology (No. 16ZR1449800) (to RZ), the Fundamental Research Funds for the Central Universities (Nos. 10247201546 and 2000219083) (to RZ), a departmental start-up fund (to LZ), the Peter and Tommy Fund, Inc., Buffalo, NY (to LZ), Funds from the University at Buffalo Community of Excellence in Genome, Environment and Microbiome (GEM) (to LZ) and UTHealth Innovation for Cancer Prevention Research Training Program Post-doctoral Fellowship (Cancer Prevention and Research Institute of Texas, grant #RP160015) (to HK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Supplementary material

11684_2018_630_MOESM1_ESM.pdf (18.4 mb)
Codes of Methods
11684_2018_630_MOESM2_ESM.pdf (121 kb)
Supplementary Table S1: Novel proton pump inhibitors with reduced adverse effect


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Copyright information

© Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Xiaoyi Li
    • 1
  • Hong Kang
    • 2
  • Wensheng Liu
    • 3
  • Sarita Singhal
    • 3
  • Na Jiao
    • 1
  • Yong Wang
    • 4
  • Lixin Zhu
    • 3
    • 5
    Email author
  • Ruixin Zhu
    • 1
    Email author
  1. 1.Department of Gastroenterology, Shanghai East Hospital, School of Life Sciences and TechnologyTongji UniversityShanghaiChina
  2. 2.School of Biomedical InformaticsThe University of Texas Health Science Center at HoustonHoustonUSA
  3. 3.Digestive Diseases and Nutrition Center, Department of PediatricsThe State University of New York at BuffaloBuffaloUSA
  4. 4.Basic Medical CollegeBeijing University of Chinese MedicineBeijingChina
  5. 5.Genome, Environment and Microbiome Community of ExcellenceThe State University of New York at BuffaloBuffaloUSA

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