Author(s):
Abdulrahman A. Humaid, Maher A. Al-Maqtari, Abdulkarim K. Alzomor, Anes A.M. Thabit
Email(s):
a.hamid@su.edu.ye , m.almaqtari@su.edu.ye , alzomor@tu.edu.ye
DOI:
10.52711/0974-360X.2024.00357
Address:
Abdulrahman A. Humaid1, Maher A. Al-Maqtari2, Abdulkarim K. Alzomor3, Anes A.M. Thabit1*
1Department of Biology, Faculty of Sciences, Sana`a University, Yemen.
2Department of Chemistry, Faculty of Sciences, Sana`a University, Yemen.
3Department of Pharmacy, Faculty of Medical Sciences, Thamar University, Yemen.
*Corresponding Author
Published In:
Volume - 17,
Issue - 5,
Year - 2024
ABSTRACT:
The aim of this study was to design and evaluate novel structural analogs of amlodipine that might have similar or higher antibacterial activity than the drug but fewer cardiovascular side effects. A number of computational and data retrieval techniques were used for the investigations in this study. After predicting the bacterial target of amlodipine, 85 structural analogs of the drug were designed and evaluated for their probability of antibacterial activity, calcium channel blocker activity, toxicity profiles, drug-likeness, and pharmacokinetics. Bacterial DNA topoisomerase I was found to be a potential target for amlodipine antibacterial activity, and thirteen analogs of the drug most likely acted on the same bacterial target as amlodipine. Of these analogs, only three had a low probability of acting as calcium channel blockers but an acceptable probability of having low toxicity and drug-likeness properties. However, only two of these analogs with a 1-butyl-4-hydropyridine core showed good probability of pharmacokinetics and are therefore promising as lead compounds for the discovery of new antibacterial drugs.
Cite this article:
Abdulrahman A. Humaid, Maher A. Al-Maqtari, Abdulkarim K. Alzomor, Anes A.M. Thabit. Amlodipine Analogs as lead compounds for the discovery of new Antibacterial drugs; A Chemoinformatics Study. Research Journal of Pharmacy and Technology. 2024; 17(5):2271-1. doi: 10.52711/0974-360X.2024.00357
Cite(Electronic):
Abdulrahman A. Humaid, Maher A. Al-Maqtari, Abdulkarim K. Alzomor, Anes A.M. Thabit. Amlodipine Analogs as lead compounds for the discovery of new Antibacterial drugs; A Chemoinformatics Study. Research Journal of Pharmacy and Technology. 2024; 17(5):2271-1. doi: 10.52711/0974-360X.2024.00357 Available on: https://www.rjptonline.org/AbstractView.aspx?PID=2024-17-5-53
REFERENCES:
1. Lagadinou M, Onisor MO, Rigas A, Musetescu DV, Gkentzi D, Assimakopoulos SF, Panos G, Marangos M. Antimicrobial Properties on Non-Antibiotic Drugs in the Era of Increased Bacterial Resistance. Antibiotics (Basel). 2020; 9(3): 107. doi.org/10.3390/antibiotics9030107
2. Laudy AE. Non-antibiotics, Efflux Pumps and Drug Resistance of Gram-negative Rods. Pol. J. Microbiol. 2022; 67(2): 129-135. doi.org/10.21307/pjm-2018-017
3. The United States Pharmacopoeia 2020: USP 43 ; The national formulary: NF 38. United States Pharmacopeial Convention.
4. Ferrari R, Pavasini R, Camici PG, Crea F, Danchin N, Pinto F, Manolis A, Marzilli M, Rosano GMC, Lopez-Sendon J, Fox K. Anti-anginal drugs-beliefs and evidence: systematic review covering 50 years of medical treatment. Eur Heart J. 2019; 40(2):190-194. doi.org/10.1093/eurheartj/ehy504
5. Wang Y.; Li X.; Wang D.; Sun, S.; Lu, C. In Vitro Interactions of Ambroxol Hydrochloride or Amlodipine in Combination with Antibacterial Agents against Carbapenem‐Resistant Acinetobacter Baumannii. Lett. Appl. Microbiol. 2019; 70(3): 189– 195. doi.org/10.1111/lam.13259
6. Hu C, Li Y, Zhao Z, Wie S, Zhao Z, Chen H, Wu P. In vitro synergistic effect of amlodipine and imipenem on the expression of AdeABC efflux pump in multidrug-resistant Acinetobacter baumanii. PLoS ONE. 2018; 13: e0198061. doi.org/ 10.1371/journal.pone.0198061
7. Mazumdar K, Ashok Kumar K, Dutta NK. Potential role of the cardiovascular non-antibiotic (helper compound) amlodipine in the treatment of microbial infections: scope and hope for the future. Int J Antimicrob Agents. 2010; 36(4): 295-302. doi.org/10.1016/j.ijantimicag.2010.05.003
8. Asok Kumar, K.; Mazumdar K., Dutta, N. K., Karak, P.; Dastidar, S. G.; Ray, R. Evaluation of Synergism between the Aminoglycoside Antibiotic Streptomycin and the Cardiovascular Agent Amlodipine. Biol. Pharm. Bull. 2004; 27(7): 1116– 1120. doi.org/10.1248/bpb.27.1116
9. Supre-Pred [Internet]. Target prediction. Available from: https://prediction.charite.de/subpages/target_prediction.php Accessed on January 1st, 2022
10. 10. Nickel J, Gohlke BO, Erehman J, Banerjee P, Rong WW, Goede A, Dunkel M, Preissner R. SuperPred: update on drug classification and target prediction. Nucleic Acids Res. 2014; 42(Web Server issue):W26-31.doi.org/10.1093/nar/gku477
11. Attique SA, Hassan M, Usman M, Atif RM, Mahboob S, Al-Ghanim KA, Bilal M, Nawaz MZ. A Molecular Docking Approach to Evaluate the Pharmacological Properties of Natural and Synthetic Treatment Candidates for Use against Hypertension. Int J Environ Res Public Health. 2019 ; 4; 16(6): 923.doi.org/10.3390/ijerph16060923
12. Alnajjar R, Mostafa A, Kandeil A, Al-Karmalawy AA. Molecular docking, molecular dynamics, and in vitro studies reveal the potential of angiotensin II receptor blockers to inhibit the COVID-19 main protease. Heliyon. 2020;6 (12): e05641. doi.org/10.1016/j.heliyon.2020.e05641
13. Ahmed A, Saeed A, Ejaz SA, Aziz M, Hashmi MZ, Channar PA, Abbas Q, Raza H, Shafiq Z, El-Seedi HR. Novel adamantyl clubbed iminothiazolidinones as promising elastase inhibitors: design, synthesis, molecular docking, ADMET and DFT studies. RSC Adv. 2022; 12(19): 11974-11991. doi.org/10.1039/d1ra09318e
14. UniProt protein database. Uni Port Knowledgebase (UniProtkb). Available from: (a):https://www.uniprot.org/uniprotkb/A0A0Q1RQC1/entry (Accessed on January 15th, 2022) (b): https://www.uniprot.org/uniprotkb/Q06AK7/entry (Accessed on January 16th, 2022) (c): https://www.uniprot.org/uniprotkb/B9EG90/entry (Accessed on April 28th, 2022)
15. Terlouw BR, Vromans SPJM, Medema MH. PIKAChU: a Python-based informatics kit for analysing chemical units. J Cheminform. 2022; 14(1): 34. doi.org/10.1186/s13321-022-00616-5
16. O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Cheminform. 2011; 3: 33.doi.org/10.1186/1758-2946-3-33
17. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF Chimera--a visualization system for exploratory research and analysis. . J Comput Chem. 2004; 25(13): 1605-1605.doi.org/10.1002/jcc.20084
18. Shaldam MA, Elhamamsy MH, Esmat EA, El-Moselhy TF. 1,4-Dihydropyridine Calcium Channel Blockers: Homology Modeling of the Receptor and Assessment of Structure Activity Relationship. ISRN Med. Chem. 2014; 2014: e203518. doi.org/10.1155/2014/203518
19. Royal Society of Chemistry-UK. ChemSpider. Structure Search.. Available from https://www.chemspider.com/StructureSearch.aspx; (Accessed on May 15th,022)
20. American Chemical Society-USA, Chemical Abstract Service's (CAS). Available from: https://scifinder-n.cas.org; (Accessed on May 17th,022)
21. National Institutes of Health (NIH)-USA, Pubchem. Available from: https://pubchem.ncbi.nlm.nih.gov; (Accessed on May 18th,2022)
22. Zhao Y, Huang G, Wu J, Wu Q, Gao S, Yan Z, Lei J, Yan N. Molecular Basis for Ligand Modulation of a Mammalian Voltage- Gated Ca2+ Channel. Cell. 2019; 177(6): 1495-1506. doi.org/10.1016/j.cell.2019.04.043
23. Tang L, Gamal El-Din TM, Swanson TM, Pryde DC, Scheuer T, Zheng N, Catterall WA. Structural Basis for Inhibition of a Voltage-Gated Ca2+ Channel by Ca2+ Antagonist Drugs. Nature. 2016; 537(7618): 117–121. doi.org/10.1038/nature19102
24. Protein Data Bank [Cited 2022 March 28]. Available from: https://www.rcsb.org/structure/5KMD.
25. Charité College of Medicine, Institute of Physiology, Structural Bioinformatics Group, Germany. ProTox II, Prediction of toxicity of Chemicals. Available from: https://tox-new.charite.de/protox_II/index.php?site=compound_input ; (Accessed on August 11th,2022)
26. Drwal MN., Banerjee P, Dunkel M, Wettig MR, Preissner R. ProTox: a web server for the in silico prediction of rodent oral toxicity. Nucleic Acids Res. 2014; 42: 53–58. doi.org/10.1093/nar/gku401
27. Swiss Institute of Bioinformatics (SIB). SwissADME. Available from: http://www.swissadme.ch/index.php ; (Accessed on October 10th,2022)
28. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017; 7: 42717.doi.org/10.1038/srep42717
29. College of Melbourne, Australia. Pharmacokinetics Computation of Small Structural Molecules (pkcsm).Available from: https://biosig.lab.uq.edu.au/pkcsm/prediction ; (Accessed on December 17th,2022)
30. Pires EV, Blundell TL, Ascher DB. PkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph- Based Signatures. Journal of Medicinal Chemistry. 2015; 58 (9): 4066–4072. doi.org/10.1021/acs.jmedchem.5b00104
31. Li D, Moorman R, Vanhercke T, Petrie J, Singh S, Jackson CJ. Classification and substrate head-group specificity of membrane fatty acid desaturases. Comput Struct Biotechnol J. 2016; 14: 341-349.doi.org/10.1016/j.csbj.2016.08.003
32. Brinster S, Lamberet G, Staels B, Trieu-Cuot P, Gruss A, Poyart C. Type II fatty acid synthesis is not a suitable antibiotic target for Gram-positive pathogens. Nature. 2009; 458: 83-86. doi.org/10.1038/nature07772
33. Tse-Dinh YC. Bacterial topoisomerase I as a target for discovery of antibacterial compounds. Nucleic Acids Res. 2009; 37(3): 731-737. doi.org/10.1093/nar/gkn936
34. US Food & Drug administration (FDA). Norvasc (Amlodipine besylate) highlights of prescription information. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019787s047lbl.pdf; (Accessed on February 24th,2022)
35. Dalhoff A.Are antibacterial effects of non‑antibiotic drugs random or purposeful because of a common evolutionary origin of bacterial and mammalian targets? Infection; 2021; 49: 569–589. doi.org/10.1007/s15010-020-01547-9
36. Ren D, Navarro B, Xu H, Yue L, Shi Q, Clapham DE. A prokaryotic voltage-gated sodium channel. Science. 2001; 294: 2372– 2375. doi.org/10.1126/science.1065635
37. Shimomura T, Yonekawa Y, Nagura H, Tateyama M, Fujiyoshi Y, Irie K. A native prokaryotic voltage-dependent calcium channel with a novel selectivity filter sequence. Elife. 2020; 25, 9: e52828. doi.org/10.7554/elife.52828
38. Pohl EE, Krylov AV, Block M, Pohl P. Changes of the membrane potential profile induced by verapamil and propranolol. Biochim Biophys Acta. 1998; 1373: 170–8. doi.org/10.1016/s0005-2736(98)00098-4
39. Chen C, Gardete S, Jansen RS, Shetty A, Dick T, Rhee KY, Dartois V. Verapamil targets membrane energetics in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2018; 62: e02107-e2117.doi.org/10.1128/aac.02107-17
40. Herbette L, Vant-Erve YMH, Rhodes D. Interaction of 1,4 dihydropyridine calcium channel antagonists with biological membranes: lipid bilayer partitioning could occur before drug binding to receptors. J Mol Cell Cardiol. 1989; 21: 187–201. doi.org/10.1016/0022-2828(89)90861-4
41. Nau R, Sörgel F, Eiffert H. Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections Clin Microbiol Rev. 2010; 23(4): 858–883.doi.org/10.1128/cmr.00007-10