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
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.
CMartín de Argila. Safety of potent gastric acid inhibition. Drugs 2005; 65(Suppl 1): 97–104
pmid: 16335863
2
DJHetzel, J Dent, WDReed, FMNarielvala, MMackinnon, JHMcCarthy, BMitchell, BRBeveridge, BHLaurence, GGGibson, AKGrant, DJCShearman, RWhitehead, PJBuckle. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 1988; 95(4): 903–912 https://doi.org/10.1016/0016-5085(88)90162-X
pmid: 3044912
3
THagiwara, K Mukaisho, TNakayama, HSugihara, THattori. Long-term proton pump inhibitor administration worsens atrophic corpus gastritis and promotes adenocarcinoma development in Mongolian gerbils infected with Helicobacter pylori. Gut 2011; 60(5): 624–630 https://doi.org/10.1136/gut.2010.207662
pmid: 21097844
4
WLiu, SS Baker, JTrinidad, ALBurlingame, RDBaker, JGForte, LPVirtuoso, NKEgilmez, LZhu. Inhibition of lysosomal enzyme activities by proton pump inhibitors. J Gastroenterol 2013; 48(12): 1343–1352 https://doi.org/10.1007/s00535-013-0774-5
pmid: 23478938
5
GPolimeni, P Cutroneo, AGallo, SGallo, ESpina, APCaputi. Rabeprazole and psychiatric symptoms. Ann Pharmacother 2007; 41(7): 1315–1317 https://doi.org/10.1345/aph.1K134
pmid: 17609230
6
ESarzynski, C Puttarajappa, YXie, MGrover, HLaird-Fick. Association between proton pump inhibitor use and anemia: a retrospective cohort study. Dig Dis Sci 2011; 56(8): 2349–2353 https://doi.org/10.1007/s10620-011-1589-y
pmid: 21318590
DWu, T Qiu, QZhang, HKang, S Yuan, LZhu, RZhu. Systematic toxicity mechanism analysis of proton pump inhibitors: an in silico study. Chem Res Toxicol 2015; 28(3): 419–430 https://doi.org/10.1021/tx5003782
pmid: 25626140
9
G.Landrum Rdkit: a software suite for cheminformatics, computational chemistry, and predictive modeling. 2013
10
LSettimo, K Bellman, RMKnegtel. Comparison of the accuracy of experimental and predicted pKa values of basic and acidic compounds. Pharm Res 2014; 31(4): 1082–1095 https://doi.org/10.1007/s11095-013-1232-z
pmid: 24249037
11
CALipinski, F Lombardo, BWDominy, PJFeeney. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001; 46(1-3): 3–26 https://doi.org/10.1016/S0169-409X(00)00129-0
pmid: 11259830
12
LOlbe, E Carlsson, PLindberg. A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole. Nat Rev Drug Discov 2003; 2(2): 132–139 https://doi.org/10.1038/nrd1010
pmid: 12563304
13
VLaw, C Knox, YDjoumbou, TJewison, ACGuo, Y Liu, AMaciejewski, DArndt, MWilson, VNeveu, ATang, G Gabriel, CLy, SAdamjee, ZTDame, BHan, Y Zhou, DSWishart. DrugBank 4.0: shedding new light on drug metabolism. Nucleic Acids Res 2014; 42(Database issue D1): D1091–D1097 https://doi.org/10.1093/nar/gkt1068
pmid: 24203711
FZhu, Z Shi, CQin, LTao, X Liu, FXu, LZhang, YSong, X Liu, JZhang, BHan, P Zhang, YChen. Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery. Nucleic Acids Res 2012; 40(Database issue): D1128–D1136 https://doi.org/10.1093/nar/gkr797
pmid: 21948793
16
JLReymond, L Ruddigkeit, LBlum, Rvan Deursen. The enumeration of chemical space. Wiley Interdiscip Rev Comput Mol Sci 2012; 2(5): 717–733 https://doi.org/10.1002/wcms.1104
17
LRuddigkeit, R van Deursen, LCBlum, JLReymond. Enumeration of 166 billion organic small molecules in the chemical universe database GDB-17. J Chem Inf Model 2012; 52(11): 2864–2875 https://doi.org/10.1021/ci300415d
pmid: 23088335
18
DSWishart, T Jewison, ACGuo, MWilson, CKnox, Y Liu, YDjoumbou, RMandal, FAziat, EDong, S Bouatra, ISinelnikov, DArndt, JXia, P Liu, FYallou, TBjorndahl, RPerez-Pineiro, REisner, FAllen, VNeveu, RGreiner, AScalbert. HMDB 3.0 — The Human Metabolome Database in 2013. Nucleic Acids Res 2013; 41(Database issue): D801–D807
pmid: 23161693
19
MKanehisa, S Goto, YSato, MFurumichi, MTanabe. KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res 2012; 40(Database issue D1): D109–D114 https://doi.org/10.1093/nar/gkr988
pmid: 22080510
20
AWiener, M Shudler, ALevit, MYNiv. BitterDB: a database of bitter compounds. Nucleic Acids Res 2012; 40(Database issue): D413–D419 https://doi.org/10.1093/nar/gkr755
pmid: 21940398
21
JAhmed, T Meinel, MDunkel, MSMurgueitio, RAdams, CBlasse, AEckert, SPreissner, RPreissner. CancerResource: a comprehensive database of cancer-relevant proteins and compound interactions supported by experimental knowledge. Nucleic Acids Res 2011; 39(Database issue suppl_1): D960–D967 https://doi.org/10.1093/nar/gkq910
pmid: 20952398
22
DWishart, D Arndt, APon, TSajed, ACGuo, Y Djoumbou, CKnox, MWilson, YLiang, JGrant, YLiu, SA Goldansaz, SMRappaport. T3DB: the toxic exposome database. Nucleic Acids Res 2015; 43(Database issue): D928–D934 https://doi.org/10.1093/nar/gku1004
pmid: 25378312
23
ELim, A Pon, YDjoumbou, CKnox, S Shrivastava, ACGuo, VNeveu, DSWishart. T3DB: a comprehensively annotated database of common toxins and their targets. Nucleic Acids Res 2010; 38(Database issue suppl_1): D781–D786 https://doi.org/10.1093/nar/gkp934
pmid: 19897546
24
HSong, Q Chu, FYan, YYang, W Han, XZheng. Red pitaya betacyanins protects from diet-induced obesity, liver steatosis and insulin resistance in association with modulation of gut microbiota in mice. J Gastroenterol Hepatol 2016; 31(8): 1462–1469 https://doi.org/10.1111/jgh.13278
pmid: 26699443
25
JCShelley, A Cholleti, LLFrye, JRGreenwood, MRTimlin, MUchimaya. Epik: a software program for pK( a ) prediction and protonation state generation for drug-like molecules. J Comput Aided Mol Des 2007; 21(12): 681–691 https://doi.org/10.1007/s10822-007-9133-z
pmid: 17899391
26
JJKlicić, RA Friesner, SYLiu, WCGuida. Accurate prediction of acidity constants in aqueous solution via density functional theory and self-consistent reaction field methods. J Phys Chem A 2002; 106(7): 1327–1335 https://doi.org/10.1021/jp012533f
27
GTBalogh, B Gyarmati, BNagy, LMolnar, GMKeseru. Comparative evaluation of in silico pK(a) prediction tools on the Gold Standard Dataset. QSAR Comb Sci 2009; 28(10): 1148–1155 https://doi.org/10.1002/qsar.200960036
28
SVellay, Miller N Latimer, GPaillard. Interactive text mining with Pipeline Pilot: a bibliographic web-based tool for PubMed. Infect Disord Drug Targets 2009; 9(3): 366–374 https://doi.org/10.2174/1871526510909030366
pmid: 19519489
CGrüber, V Buss. Quantum-mechanically calculated properties for the development of quantitative structure-activity relationships (QSAR’S). pKa-values of phenols and aromatic and aliphatic carboxylic acids. Chemosphere 1989; 19(10-11): 1595–1609 https://doi.org/10.1016/0045-6535(89)90503-1
GRBickerton, GV Paolini, JBesnard, SMuresan, ALHopkins. Quantifying the chemical beauty of drugs. Nat Chem 2012; 4(2): 90–98 https://doi.org/10.1038/nchem.1243
pmid: 22270643
33
STian, J Wang, YLi, DLi, L Xu, THou. The application of in silico drug-likeness predictions in pharmaceutical research. Adv Drug Deliv Rev 2015; 86: 2–10 https://doi.org/10.1016/j.addr.2015.01.009
pmid: 25666163
34
CDurand, KC Willett, ARDesilets. Proton pump inhibitor use in hospitalized patients: is overutilization becoming a problem? Clin Med Insights Gastroenterol 2012; 5: CGast. S9588 https://doi.org/10.4137/CGast.S9588
pmid: 24833936