In-silico Study of the Developed Hydroxychloroquine-based ACE2 Inhibitor Molecules Against COVID-19: Molecular Modeling and Docking
Published online first on August 11, 2021.
In the present study, we will verify the action of hydroxychloroquine-based derivatives on ACE2 which is considered to be the main portal of entry of the SARS-CoV-2 virus and constitutes an exciting target given its relative genetic stability compared to viral proteins. Thus, 81 molecules derived from hydroxychloroquine by substitutions at 4 different positions were generated in-silico and then studied for their affinity for ACE2 by molecular docking. Only 4 molecules were retained because of their affinity and bioavailability demonstrated by molecular dynamics and molecular docking calculations using COSMOtherm and Materials Studio software.
Keywords:Hydroxychloroquine, molecular modeling, Covid-19, ACE2, affinity
Y. Acosta-Ampudia et al., "COVID-19 convalescent plasma composition and immunological effects in severe patients," Journal of Autoimmunity, vol. 118, Mar. 2021, Art. no. 102598. DOI: https://doi.org/10.1016/j.jaut.2021.102598
B. B. Chomel, A. Belotto, and F.-X. Meslin, "Wildlife, Exotic Pets, and Emerging Zoonoses," Emerging Infectious Diseases, vol. 13, no. 1, pp. 6–11, Jan. 2007. DOI: https://doi.org/10.3201/eid1301.060480
G. Pullano, F. Pinotti, E. Valdano, P.-Y. Boelle, C. Poletto, and V. Colizza, "Novel coronavirus (2019-nCoV) early-stage importation risk to Europe, January 2020," Eurosurveillance, vol. 25, no. 4, Jan. 2020, Art. no. 2000057. DOI: https://doi.org/10.2807/1560-7917.ES.2020.25.4.2000057
C. Scagnolari et al., "Differential induction of type I and III interferon genes in the upper respiratory tract of patients with coronavirus disease 2019 (COVID-19)," Virus Research, vol. 295, Apr. 2021, Art. no. 198283. DOI: https://doi.org/10.1016/j.virusres.2020.198283
L. I. Oztig and O. E. Askin, "Human mobility and coronavirus disease 2019 (COVID-19): a negative binomial regression analysis," Public Health, vol. 185, pp. 364–367, Aug. 2020. DOI: https://doi.org/10.1016/j.puhe.2020.07.002
M. Nimgampalle, V. Devanathan, and A. Saxena, "Screening of Chloroquine, Hydroxychloroquine and its derivatives for their binding affinity to multiple SARS-CoV-2 protein drug targets," Journal of Biomolecular Structure and Dynamics, pp. 1–13, Jun. 2020. DOI: https://doi.org/10.26434/chemrxiv.12365282.v1
M. Wang et al., "Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro," Cell Research, vol. 30, no. 3, pp. 269–271, Mar. 2020. DOI: https://doi.org/10.1038/s41422-020-0282-0
K. Lestari, T. Sitorus, S. Megantara, and J. Levita, "Molecular docking of quinine, chloroquine and hydroxychloroquine to angiotensin converting enzyme 2 (ACE2) receptor for discovering new potential COVID-19 antidote," Journal of Advanced Pharmacy Education and Research, vol. 10, no. 2, pp. 1–4, Jan. 2020.
R. Badraoui, M. Adnan, F. Bardakci, and M. M. Alreshidi, "Chloroquine and Hydroxychloroquine Interact Differently with ACE2 Domains Reported to Bind with the Coronavirus Spike Protein: Mediation by ACE2 Polymorphism," Molecules, vol. 26, no. 3, Jan. 2021, Art. no. 673. DOI: https://doi.org/10.3390/molecules26030673
F. Li, W. Li, M. Farzan, and S. C. Harrison, "Structure of SARS Coronavirus Spike Receptor-Binding Domain Complexed with Receptor," Science, vol. 309, no. 5742, pp. 1864–1868, Sep. 2005. DOI: https://doi.org/10.1126/science.1116480
W. Li et al., "Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2," The EMBO Journal, vol. 24, no. 8, pp. 1634–1643, Apr. 2005. DOI: https://doi.org/10.1038/sj.emboj.7600640
M. Hussain et al., "Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein," Journal of Medical Virology, vol. 92, no. 9, pp. 1580–1586, 2020. DOI: https://doi.org/10.1002/jmv.25832
A. E. Shikov et al., "Analysis of the Spectrum of ACE2 Variation Suggests a Possible Influence of Rare and Common Variants on Susceptibility to COVID-19 and Severity of Outcome," Frontiers in Genetics, vol. 11, Sep. 2020, Art. no. 551220. DOI: https://doi.org/10.3389/fgene.2020.551220
F. Ali, M. Elserafy, M. H. Alkordi, and M. Amin, "ACE2 coding variants in different populations and their potential impact on SARS-CoV-2 binding affinity," Biochemistry and Biophysics Reports, vol. 24, Dec. 2020, Art. no. 100798. DOI: https://doi.org/10.1016/j.bbrep.2020.100798
A. Novelli et al., "Analysis of ACE2 genetic variants in 131 Italian SARS-CoV-2-positive patients," Human Genomics, vol. 14, no. 1, Sep. 2020, Art. no. 29. DOI: https://doi.org/10.1186/s40246-020-00279-z
E. E. Y. Cotrina et al., "Optimization of kinetic stabilizers of tetrameric transthyretin: A prospective ligand efficiency-guided approach," Bioorganic & Medicinal Chemistry, vol. 28, no. 23, Dec. 2020, Art. no. 115794. DOI: https://doi.org/10.1016/j.bmc.2020.115794
X. Jiang, S. Li, H. Zhang, and L.-L. Wang, "Discovery of potentially biased agonists of mu-opioid receptor (MOR) through molecular docking, pharmacophore modeling, and MD simulation," Computational Biology and Chemistry, vol. 90, Feb. 2021, Art. no. 107405. DOI: https://doi.org/10.1016/j.compbiolchem.2020.107405
M. P. Edwards and D. A. Price, "Chapter 23 - Role of Physicochemical Properties and Ligand Lipophilicity Efficiency in Addressing Drug Safety Risks," in Annual Reports in Medicinal Chemistry, vol. 45, J. E. Macor, Ed. Cambridge, MA, USA: Academic Press, 2010, pp. 380–391. DOI: https://doi.org/10.1016/S0065-7743(10)45023-X
B. Takahashi et al., "2-Aminoalkyl nicotinamide derivatives as pure inverse agonists of the ghrelin receptor," Bioorganic & Medicinal Chemistry Letters, vol. 25, no. 13, pp. 2707–2712, Jul. 2015. DOI: https://doi.org/10.1016/j.bmcl.2015.04.040
S.-M. Lee et al., "Calcitonin Receptor N-Glycosylation Enhances Peptide Hormone Affinity by Controlling Receptor Dynamics," Journal of Molecular Biology, vol. 432, no. 7, pp. 1996–2014, Mar. 2020. DOI: https://doi.org/10.1016/j.jmb.2020.01.028
M. Hassan et al., "Exploration of synthetic multifunctional amides as new therapeutic agents for Alzheimer’s disease through enzyme inhibition, chemoinformatic properties, molecular docking and dynamic simulation insights," Journal of Theoretical Biology, vol. 458, pp. 169–183, Dec. 2018. DOI: https://doi.org/10.1016/j.jtbi.2018.09.018
R. Madaj, R. Pawlowska, and A. Chworos, "In silico exploration of binding of selected bisphosphonate derivatives to placental alkaline phosphatase via docking and molecular dynamics," Journal of Molecular Graphics and Modelling, vol. 103, Mar. 2021, Art. no. 107801. DOI: https://doi.org/10.1016/j.jmgm.2020.107801
K. A, "Conductor-Like Screening Model for Real Solvents - A New Approach to the Quantitative Calculation of Solvation Phenomena," Journal of Physical Chemistry, vol. 99, no. 7, pp. 2224–2235, 1995. DOI: https://doi.org/10.1021/j100007a062
Y. Bhalla, K. Chadha, R. Chadha, and M. Karan, "Daidzein cocrystals: An opportunity to improve its biopharmaceutical parameters," Heliyon, vol. 5, no. 11, Nov. 2019, Art. no. e02669. DOI: https://doi.org/10.1016/j.heliyon.2019.e02669
S. Sharma, "Overview of BIOVIA Materials Studio, LAMMPS, and GROMACS," in Molecular Dynamics Simulation of Nanocomposites using BIOVIA Materials Studio, Lammps and Gromacs, Amsterdam, Netherlands: Elsevier, 2019, pp. 39–100. DOI: https://doi.org/10.1016/B978-0-12-816954-4.00002-4
M. B. Miller, D.-L. Chen, H.-B. Xie, D. R. Luebke, J. Karl Johnson, and R. M. Enick, "Solubility of CO2 in CO2-philic oligomers; COSMOtherm predictions and experimental results," Fluid Phase Equilibria, vol. 287, no. 1, pp. 26–32, Dec. 2009. DOI: https://doi.org/10.1016/j.fluid.2009.08.022
S. Ma, J. Liu, W. Xu, F. Sun, J. Jiang, and L. Sun, "Experiment and simulation for CO2 capture using low transition temperature mixtures as solvents," International Journal of Greenhouse Gas Control, vol. 103, p. 103178, Dec. 2020. DOI: https://doi.org/10.1016/j.ijggc.2020.103178
K. E. Kanouni, Y. Benguerba, and A. Erto, "Theoretical investigation of the solubility of some antiemetic drugs," Journal of Molecular Liquids, vol. 282, pp. 626–632, May 2019. DOI: https://doi.org/10.1016/j.molliq.2019.03.028
F. O. Farias, J. F. B. Pereira, J. A. P. Coutinho, L. Igarashi-Mafra, and M. R. Mafra, "Understanding the role of the hydrogen bond donor of the deep eutectic solvents in the formation of the aqueous biphasic systems," Fluid Phase Equilibria, vol. 503, Jan. 2020, Art. no. 112319. DOI: https://doi.org/10.1016/j.fluid.2019.112319
A. S. Kote and D. V. Wadkar, "Modeling of Chlorine and Coagulant Dose in a Water Treatment Plant by Artificial Neural Networks," Engineering, Technology & Applied Science Research, vol. 9, no. 3, pp. 4176–4181, Jun. 2019. DOI: https://doi.org/10.48084/etasr.2725
W. M. A. W. Ahmad, R. A. A. Rohim, Y. Norhayati, N. A. Aleng, and Z. Ali, "Developing A New Dimension of an Applied Exponential Model: Application in Biological Sciences," Engineering, Technology & Applied Science Research, vol. 8, no. 4, pp. 3130–3134, Aug. 2018. DOI: https://doi.org/10.48084/etasr.2124
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