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In silico design of novel proton-pump inhibitors with reduced adverse effects |
Xiaoyi Li1, Hong Kang2, Wensheng Liu3, Sarita Singhal3, Na Jiao1, Yong Wang4, Lixin Zhu3,5(), Ruixin Zhu1() |
1. Department of Gastroenterology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China 2. School of Biomedical Informatics, The University of Texas Health Science Center at Houston, 7000 Fannin St, Houston, TX 77030, USA 3. Digestive Diseases and Nutrition Center, Department of Pediatrics, The State University of New York at Buffalo, Buffalo, NY 14260, USA 4. Basic Medical College, Beijing University of Chinese Medicine, Beijing 100029, China 5. Genome, Environment and Microbiome Community of Excellence, The State University of New York at Buffalo, Buffalo, NY 14214, USA |
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Abstract 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.
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Keywords
proton-pump inhibitor
adverse effect
pharmacological mechanism
toxicological mechanism
pKa calculation
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Corresponding Author(s):
Lixin Zhu,Ruixin Zhu
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Just Accepted Date: 24 April 2018
Online First Date: 31 May 2018
Issue Date: 28 March 2019
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