Molecular Docking Investigation, Pharmacokinetic Analysis, and Molecular Dynamic Simulation of Some Benzoxaborole-Benzimidazole Hybrids: An Approach to Identifying Superior Onchocerca Inhibitors
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Submitted
20 August 2022
Published
28 February 2023
Keywords:
-
pharmacokinetics, molecular dynamics, Molecular docking, Onchocerciasis, Benzimidazole-benzoxaborole, Flubendazole
Abstract
Onchocerciasis is one of the major neglected tropical diseases caused by the filarial worm (Onchocerca volvulus), affecting an estimated population of about 37 million people living predominantly in tropical Africa. The major treatment approach has been based on the use of Ivermectin, which kills the microfilariae or the less effective Doxycycline targeting Wolbachia, endosymbiont of filarial nematodes. Flubendazole (FBZ) has proved effective in treating adult worms but with threatening adverse effects. Against this backdrop, therefore, a combined molecular docking study and pharmacokinetic screening were conducted on a series of benzimidazole-benzoxaborole hybrids to find more potent analogs with attributes that address the limitations of existing therapies. All the nineteen analogs were found to possess better docking scores than the reference drug (FBZ, Moldock scores = -120.466 and -125.359). The results of pharmacokinetic testing suggest that four molecules (14, 16, 19, and 20) are orally bioavailable and showed better ADMET properties than FBZ. These molecules and FBZ showed good binding interactions with the receptors’ active sites. Also, the molecular dynamic simulation performed on the docked complexes of 20 and FBZ confirmed the rigidity and stability of their interactions. Based on the results of this study, the selected molecules (especially 20) could be considered superior drug candidates for the treatment of Onchocerciasis.
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References
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24. Wang X, Dong H, Qin Q. QSAR models on aminopyrazole-substituted resorcylate compounds as Hsp90 inhibitors. J Comput Sci Eng. 2020;48:1146-56.
25. Ugbe FA, Shallangwa GA, Uzairu A, Abdulkadir I. Theoretical activity prediction, structure-based design, molecular docking and pharmacokinetic studies of some maleimides against Leishmania donovani for the treatment of leishmaniasis. Bull Natl Res Cent. 2020;46:92. doi:10.1186/s42269-022-00779-z
26. Abdullahi SA, Uzairu A, Shallangwa GA, Uba S, Umar AB. In-silico activity prediction, structure-based drug design, molecular docking and pharmacokinetic studies of selected quinazoline derivatives for their antiproliferative activity against triple negative breast cancer (MDA-MB231) cell line. Bull Natl Res Cent. 2022;46:2. doi:10.1186/s42269-021-00690-z
27. Sun Y, Yang AW, Hung A, Lenon GB. Screening for a Potential Therapeutic Agent from the Herbal Formula in the 4th Edition of the Chinese National Guidelines for the Initial-Stage Management of COVID-19 via Molecular Docking. Evid Based Complement Alternat Med. 2020:3219840. doi:10.1155/2020/3219840
28. Abraham MJ, Gready JE. Optimization of parameters for molecular dynamics simulation using smooth particle-mesh Ewald in GROMACS 4.5. J Comput Chem. 2011;32(9):2031-40. doi:10.1002/jcc.21773
29. Bai Q, Tan S, Xu T, Liu H, Huang J, Yao X. MolAICal: a soft tool for 3D drug design of protein targets by artificial intelligence and classical algorithm. Brief Bioinformatics. 2020;22(3):bbaa161. doi:10.1093/bib/bbaa161
30. Edache EI, Uzairu A, Mamza PA, Shallangwa GA. A Comparative QSAR Analysis, 3D-QSAR, Molecular Docking And Molecular Design Of Iminoguanidine-Based Inhibitors Of HemO: A Rational Approach To Antibacterial Drug Design. J Drugs Pharm Sci. 2020;4(3):21-36. doi:10.31248/JDPS2020.036
31. Ugbe FA, Shallangwa GA, Uzairu A, Abdulkadir I. A 2-D QSAR Modeling, Molecular Docking Study and Design of 2-Arylbenzimidazole Derivatives as Novel Leishmania Inhibitors: A Molecular Dynamics Study. Adv J Chem Sect A. 2023;6(1):50-64. doi:10.22034/ajca.2023.365873.1337
2. Ugbe FA, Shallangwa GA, Uzairu A, Abdulkadir I. Theoretical modeling and design of some pyrazolopyrimidine derivatives as Wolbachia inhibitors, targeting lymphatic filariasis and onchocerciasis. In Silico Pharmacol. 2022;10(1):8. doi:10.1007/s40203-022-00123-3
3. Metuge JA, Nyongbela KD, Mbah JA. Anti-Onchocerca activity and phytochemical analysis of an essential oil from Cyperus articulatus L. BMC Complement Altern Med. 2014;14:223. doi:10.1186/1472-6882-14-223
4. Samje M, Metuge J, Mbah J, B. Nguesson, Cho-Ngwa F. In vitro anti-Onchocerca ochengi activities of extracts and chromatographic fractions of Craterispermum laurinum and Morinda lucida. BMC Complement Altern Med. 2014;14:325. doi:10.1186/1472-6882-14-325
5. Metuge JA, Babiaka SB, Mbah JA, Ntie-Kang F, Ayimele GA, Cho-Ngwa F. Anti-onchocerca Metabolites from Cyperus articulatus: Isolation, In Vitro Activity and In Silico 'Drug-Likeness'. Nat Prod Bioprospect. 2014;4(4):243-9. doi:10.1007/s13659-014-0023-5
6. McGillan P, Berry NG, Nixon L, Leung SC, Webborn PJH, Wenlock MC, et al. Development of Pyrazolopyrimidine Anti-Wolbachia Agents for the Treatment of Filariasis. ACS Med Chem Lett. 2021;12(9):1421–6. doi:10.1021/acsmedchemlett.1c00216
7. Sungpradit S, Sanprasert V. Lymphatic filariasis. In Misra G, Srivastava V, editors. Molecular Advancements in Tropical Diseases Drug Discovery. Amsterdam: Elsevier; 2020. p. 65–94. doi:10.1016/B978-0-12-821202-8.00004-9
8. Sainas S, Dosio F, Boschi D, Lolli ML. Targeting Human Onchocerciasis: Recent Advances Beyond Ivermectin. Annu Rep Med Chem. 2018;51:1-38. doi:10.1016/bs.armc.2018.08.001
9. Akama T, Freund YT, Berry P, Carter DE, Easom E, Jarnagin K, et al. Macrofilaricidal Benzimidazole–Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 1. Amide Linked Analogs ACS Infect Dis. 2020;6(2):173-9. doi:10.1021/acsinfecdis.9b00396
10. Carter DS, Jacobs RT, Freund Y, Berry P, Akama T, Easom EE, et al. Macrofilaricidal Benzimidazole–Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 2. Ketone Linked Analogs. ACS Infect Dis. 2020;6(2):180-5. doi:10.1021/acsinfecdis.9b00397
11. Adeniji SE, Arthur DE, Abdullahi M, Abdullahi A, Ugbe FA. Computer-aided modeling of triazole analogues, docking studies of the compounds on DNA gyrase enzyme and design of new hypothetical compounds with efficient activities. J Biomol Struct Dyn. 2020;40(9):4004-20. doi:10.1080/07391102.2020.1852963
12. Ibrahim MT, Uzairu A, Shallangwa GA, Uba S. Lead Identification of Some Anti-Cancer Agents with Prominent Activity Against Non-small Cell Lung Cancer (NSCLC) and Structure-Based Design. Chem Afr. 2020;3:1023–44. doi:10.1007/s42250-020-00191-y
13. Ugbe FA, Shallangwa GA, Uzairu A, Abdulkadir I. Activity modeling, molecular docking and pharmacokinetic studies of some boron-pleuromutilins as anti-wolbachia agents with potential for treatment of filarial diseases. Chem Data Collect. 2021;36:100783. doi:10.1016/j.cdc.2021.100783
14. Ibrahim MT, Uzairu A, Uba S, Shallangwa GA. Design of more potent quinazoline derivatives as EGFRWT inhibitors for the treatment of NSCLC: a computational approach. Future J Pharm Sci. 2021;7:140. doi:10.1186/s43094-021-00279-3
15. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. 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. doi:10.1016/s0169-409x(00)00129-0
16. Edache EI, Uzairu A, Mamza PA, Shallangwa GA. Computational modeling and analysis of the Theoretical structure of Thiazolino 2-pyridone amide inhibitors for Yersinia pseudotuberculosis and Chlamydia trachomatis Infectivity. Bull Sci Res. 2022;4(1):14-39. doi:10.54392/bsr2212
17. Perbandt M, Höppner J, Burmeister C, Lüersen K, Betzel C, Liebau E. Structure of the extracellular glutathione S-transferase OvGST1 from the human pathogenic parasite Onchocerca volvulus. J Mol Biol. 2008;377(2):501–11. doi:10.1016/j.jmb.2008.01.029
18. Perbandt M, Höppner J, Betzel C, Walter RD, Liebau E. Structure of the major cytosolic glutathione S-transferase from the parasitic nematode Onchocerca volvulus. J Biol Chem. 2005;280(13):12630-6. doi:10.1074/jbc.m413551200
19. Baell JB, Holloway GA. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem. 2010;53(7):2719-40. doi:10.1021/jm901137j
20. Pires DE, Blundell TL, Ascher DB. pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. J Med Chem. 2015;58(9):4066-72. doi:10.1021/acs.jmedchem.5b00104
21. Yang H, Lou C, Sun L, Li J, Cai Y, Wang, Z, et al. admetSAR 2.0: web-service for prediction and optimization of chemical ADMET properties. Bioinformatics. 2019;35(6):1067-9. doi:10.1093/bioinformatics/bty707
22. 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(1):42717. doi:10.1038/srep42717
23. Lee J, Cheng X, Swails JM, Yeom MS, Eastman PK, Lemkul JA, et al. CH CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. J Chem Theory Comput. 2016;12(1):405-13. doi:10.1021/acs.jctc.5b00935
24. Wang X, Dong H, Qin Q. QSAR models on aminopyrazole-substituted resorcylate compounds as Hsp90 inhibitors. J Comput Sci Eng. 2020;48:1146-56.
25. Ugbe FA, Shallangwa GA, Uzairu A, Abdulkadir I. Theoretical activity prediction, structure-based design, molecular docking and pharmacokinetic studies of some maleimides against Leishmania donovani for the treatment of leishmaniasis. Bull Natl Res Cent. 2020;46:92. doi:10.1186/s42269-022-00779-z
26. Abdullahi SA, Uzairu A, Shallangwa GA, Uba S, Umar AB. In-silico activity prediction, structure-based drug design, molecular docking and pharmacokinetic studies of selected quinazoline derivatives for their antiproliferative activity against triple negative breast cancer (MDA-MB231) cell line. Bull Natl Res Cent. 2022;46:2. doi:10.1186/s42269-021-00690-z
27. Sun Y, Yang AW, Hung A, Lenon GB. Screening for a Potential Therapeutic Agent from the Herbal Formula in the 4th Edition of the Chinese National Guidelines for the Initial-Stage Management of COVID-19 via Molecular Docking. Evid Based Complement Alternat Med. 2020:3219840. doi:10.1155/2020/3219840
28. Abraham MJ, Gready JE. Optimization of parameters for molecular dynamics simulation using smooth particle-mesh Ewald in GROMACS 4.5. J Comput Chem. 2011;32(9):2031-40. doi:10.1002/jcc.21773
29. Bai Q, Tan S, Xu T, Liu H, Huang J, Yao X. MolAICal: a soft tool for 3D drug design of protein targets by artificial intelligence and classical algorithm. Brief Bioinformatics. 2020;22(3):bbaa161. doi:10.1093/bib/bbaa161
30. Edache EI, Uzairu A, Mamza PA, Shallangwa GA. A Comparative QSAR Analysis, 3D-QSAR, Molecular Docking And Molecular Design Of Iminoguanidine-Based Inhibitors Of HemO: A Rational Approach To Antibacterial Drug Design. J Drugs Pharm Sci. 2020;4(3):21-36. doi:10.31248/JDPS2020.036
31. Ugbe FA, Shallangwa GA, Uzairu A, Abdulkadir I. A 2-D QSAR Modeling, Molecular Docking Study and Design of 2-Arylbenzimidazole Derivatives as Novel Leishmania Inhibitors: A Molecular Dynamics Study. Adv J Chem Sect A. 2023;6(1):50-64. doi:10.22034/ajca.2023.365873.1337
Authors
1.
Ugbe FA, Shallangwa GA, Uzairu A, Abdulkadir I. Molecular Docking Investigation, Pharmacokinetic Analysis, and Molecular Dynamic Simulation of Some Benzoxaborole-Benzimidazole Hybrids: An Approach to Identifying Superior Onchocerca Inhibitors. Borneo J Pharm [Internet]. 2023Feb.28 [cited 2025Apr.2];6(1):58-7. Available from: https://ojs.umpr.ac.id/bjop/article/view/3876
Copyright (c) 2023 Fabian Audu Ugbe, Gideon Adamu Shallangwa, Adamu Uzairu, Ibrahim Abdulkadir
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