A Computational Study of Ivermectin and Doxycycline Combination Drug Against SARS-CoV-2 Infection
Dr Meenakshi Rana, Pooja Yadav, Papia Chowdhury
doi:10.21203/rs.3.rs-755838/v1
In the present study, we have described how by using molecular docking and molecular dynamics (MD) simulation studies the combination drug of ivermectin and doxycycline can be used as a potential inhibitor for Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) virus. In lieu of unavailability of specific cure of coronavirus disease of 2019 (COVID-19) till now various possibilities for individual and combination drugs have been explored by the medical practitioners/scientists for the remedial purpose of CoV-2 infections. 3C-like protease (3CL pro ) is the main protease of SARS-CoV-2 virus which plays an essential role in mediating viral replication in the human body. 3CL pro protein can serve as an attractive drug target. In this work, we have studied drug: 3CL pro interactions by in-silico molecular docking and MD simulation approaches. Common and easily available antiviral drugs ivermectin, doxycycline and their combination can regulate 3CL pro protein's function due to its easy inhibition.
docked pose position (Table 2 ). For doxycycline: protein complex, pose 7 is the better interacted position with the binding affinity of -6.4 kcal/mol, dreiding energy; 6,063.5, dipole moment; 6.104 Debye, inhibition constant; 2.0 X 10 -5 M and 7 number of hydrogen bonds (Table 2 ). Best pose of the donor-acceptor surface with their possible hydrogen bonding and hydrophobic interactions 3D and 2D view are shown in Figure 3b . Our result shows that out of two possible ligand drug structures, ivermectin represents the best potentiality to inhibit with the SARS 3CL pro (6LU7) by its best docking affinity compared to the doxycycline. Good binding mode of interactions of ivermectin: protein complex also verified by its less binding energy, minimum inhibition constant value as compared to doxycycline. Both the drug molecules showed good stability as a complex with the targeted protein. These drug molecules also satisfy the required drug likeness properties according to Ro5, Veber etc. rules, polar surface areas and logP values. RMSD corresponds to any change in the conformational stability of the protein: drug complex and in the protein dynamics. RMSD of the free protein and protein: ligand complex have been simulated to 100000 psby using MD simulations. RMSD and RMSF have been measured by using the GROMACS module at an interval of 1000 ps. RMSD variation of apo 3CL pro lies in the range from 0.08 to 0.16Å. Ivermectin: 3CL pro , doxycycline: 3CL pro , ivermectin+doxycycline: 3CL..
References
Alout, Foy, Ivermectin: a complimentary weapon against the spread of malaria?. Expert review of anti-infective therapy
Anand, Ziebuhr, Wadhwani, Mesters, Hilgenfeld, Coronavirus main proteinase (3CL pro ) structure: basis for design of anti-SARS drugs, Science
Baildya, Ghosh, Chattopadhyay, Ap, Inhibitory capacity of Chloroquine against SARS-COV-2 by effective binding with Angiotensin converting enzyme-2 receptor: An insight from molecular docking and MD-simulation studies, Journal of Molecular Structure
Baildya, Khan, Ghosh, Dutta, Chattopadhyay, Screening of potential drug from Azadirachta Indica (Neem) extracts for SARS-CoV-2: An insight from molecular docking and MDsimulation studies, Journal of molecular structure
Belouzard, Millet, Licitra, Whittaker, Mechanisms of coronavirus cell entry mediated by the viral spike protein, Viruses
Benson, Daggett, A comparison of multiscale methods for the analysis of molecular dynamics simulations, The Journal of Physical Chemistry B
Berendsen, Postma, Van Gunsteren, Dinola, Haak, Molecular dynamics with coupling to an external bath, The Journal of chemical physics
Berendsen, Van Der Spoel, Van Drunen, GROMACS: a message-passing parallel molecular dynamics implementation, Computer physics communications
Bhowmick, Dang, Vallish, Dang, Safety and Efficacy of Ivermectin and Doxycycline Monotherapy and in Combination in the Treatment of COVID-19: A Scoping Review, Drug safety
Burley, Berman, Bhikadiya, Bi, Chen et al., RCSB Protein Data Bank: biological macromolecular structures enabling research and education in fundamental biology, biomedicine, biotechnology and energy, Nucleic acids research
Cardoso, Mendanha, Molecular dynamics simulation of docking structures of SARS-CoV-2 main protease and HIV protease inhibitors, Journal of molecular structure
Chowdhury, In silico investigation of phytoconstituents from Indian medicinal herb 'Tinosporacordifolia (giloy)'against SARS-CoV-2 (COVID-19) by molecular dynamics approach, Journal of Biomolecular Structure and Dynamics
Chowdhury, Pathak, Neuroprotective Immunity by Essential Nutrient "Choline" for the Prevention of SARS CoV2 Infections: An In Silico Study by Molecular Dynamics Approach, Chemical Physics Letters
Dassaultsystemes, Discovery studio modeling environment
Dennington, Keith, Millam, Gauss View
Dobson, Whitley, Pocock, Monto, Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials, The Lancet
Drożdżal, Rosik, Lechowicz, Machaj, Kotfis et al., FDA approved drugs with pharmacotherapeutic potential for SARS-CoV-2 (COVID-19) therapy, Drug resistance updates
Dyall, Gross, Kindrachuk, Johnson, Olinger et al., Middle East respiratory syndrome and severe acute respiratory syndrome: current therapeutic options and potential targets for novel therapies, Drugs
Estola, Coronaviruses, a new group of animal RNA viruses, Avian Dis
Frisch, Gaussian 09, Revision B.01
Gendrot, Andreani, Jardot, Hutter, Delandre et al., In vitro antiviral activity of doxycycline against SARS-CoV-2, Molecules,
doi:10.3390/molecules25215064Gorbalenya, Baker, Baric, Groot, Drosten et al., and its viruses-a statement of the Coronavirus Study Group
Graham, Donaldson, Baric, A decade after SARS: strategies for controlling emerging coronaviruses, Nature Reviews Microbiology
Guo, Cao, Hong, Tan, Chen et al., The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak-an update on the status, Military Medical Research
Hendaus, Jomha, Covid-19 induced superimposed bacterial infection, Journal of Biomolecular Structure and Dynamics
Huang, Wang, Li, Ren, Zhao et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, The lancet
Hung, Lung, Tso, Liu, Chung et al., Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial, The Lancet
Jairajpuri, Hussain, Nasreen, Mohammad, Anjum et al., Identification of natural compounds as potent inhibitors of SARS-CoV-2 main protease using combined docking and molecular dynamics simulations, Saudi Journal of Biological Sciences
Jin, Du, Xu, Deng, Liu et al., Structure of M pro from SARS-CoV-2 and discovery of its inhibitors, Nature
Kelleni, Nitazoxanide/azithromycin combination for COVID-19: A suggested new protocol for early management, Pharmacological research
Khan, Zia, Ashraf, Uddin, Ul-Haq, Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach, Journal of Biomolecular Structure and Dynamics,
doi:10.1080/07391102.2020.1751298Kircik, Rosso, Layton, Schauber, Over 25 years of clinical experience with ivermectin: an overview of safety for an increasing number of indications, J Drugs Dermatol
Km, Tanase, Richard, Cao, Hederer et al., Indacaterol acetate/mometasonefuroate provides sustained improvements in lung function compared with salmeterolxinafoate/fluticasone propionate in patients with moderate-tovery-severe COPD: results from a Phase II randomized, double-blind 12-week study, International Journal of Chronic Obstructive Pulmonary Disease
Kumari, Kumar, Open Source Drug Discovery Consortium, Lynn A. g_mmpbsa A GROMACS tool for high-throughput MM-PBSA calculations, Journal of chemical information and modeling
Leong, Ang, Earnest, Teoh, Xu et al., Investigational use of ribavirin in the treatment of severe acute respiratory syndrome, Singapore, 2003, Tropical Medicine & International Health
Leong, Chan, Khan, Oon, Sy et al., Virus-specific RNA and antibody from convalescent-phase SARS patients discharged from hospital, Emerging infectious diseases
Liu, Lin, Ho, Chen, Homology models of main proteinase from coronavirus, Chem. Phys. Lett
Lv, Ren, Chen, Wu, Chen, Application of CRISPRi for prokaryotic metabolic engineering involving multiple genes, a case study: controllable P (3HB-co-4HB) biosynthesis, Metabolic engineering
Mcintosh, Chao, Krause, Wasil, Mocega et al., Coronavirus infection in acute lower respiratory tract disease of infants, Journal of Infectious Diseases
Mercorelli, Palù, Loregian, Drug repurposing for viral infectious diseases: how far are we?, Trends in microbiology
Muralidharan, Sakthivel, Velmurugan, Gromiha, Computational studies of drug repurposing and synergism of lopinavir, oseltamivir and ritonavir binding with SARS-CoV-2 Protease against COVID-19, Journal of Biomolecular Structure and Dynamics
Panyod, Ho, Sheen, Dietary therapy and herbal medicine for COVID-19 prevention: A review and perspective, Journal of Traditional and Complementary Medicine
Poulopoulos, Waters, Carbidopa/levodopa/entacapone: the evidence for its place in the treatment of Parkinson's disease, Core evidence
Rana, Chowdhury, Perturbation of hydrogen bonding in hydrated pyrrole-2-carboxaldehyde complexes, Journal of molecular modeling
Rana, Chowdhury, Studies on Size Dependent Structures and Optical Properties of CdSeS Clusters, Journal of Cluster Science
Rota, Oberste, Monroe, Nix, Campagnoli et al., Characterization of a novel coronavirus associated with severe acute respiratory syndrome, science
Sanner, Python: a programming language for software integration and development, J Mol Graph Model
Smitha, Mary, Mary, Serdaroglu, Chowdhury et al., Modeling the DFT structural and reactivity studies of a pyrimidine-6-carboxylate derivative with reference to its wavefunction-dependent, MD simulations and evaluation for potential antimicrobial activity, Journal of Molecular Structure
Su, Wong, Shi, Liu, Lai et al., Epidemiology, genetic recombination, and pathogenesis of coronaviruses, Trends in microbiology
Trott, Olson, AutoDockVina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, J. Comput. Chem
Van Der Hoek, Pyrc, Jebbink, Vermeulen-Oost, Berkhout et al., Identification of a new human coronavirus, Nature medicine
Vangunsteren, Billeter, Eising, Hünenberger, Krüger et al., Biomolecular simulation: the GROMOS96 manual and user guide
Verma, Kumar, Singh, Goswami, Camps et al., Repurposing potential of Ayurvedic medicinal plants derived active principles against SARS-CoV-2 associated target proteins revealed by molecular docking, molecular dynamics and MM-PBSA studies, Biomedicine & Pharmacotherapy
Wang, Guo, Ling, Ji, Niu et al., The chronic adverse effect of chloroquine on kidney in rats through an autophagy dependent and independent pathways, Nephron
Whittaker, Varela, Broderick, Seddon, Examining the complex relationship between tuberculosis and other infectious diseases in children: a review, Frontiers in pediatrics
Xue, Li, Xie, Wang, Review of drug repositioning approaches and resources, International journal of biological sciences
Yiğit, Yardım, Çelebi, Levent, Şentürk, Graphene/Nafion composite film modified glassy carbon electrode for simultaneous determination of paracetamol, aspirin and caffeine in pharmaceutical formulations, Talanta
Yuriev, Agostino, Ramsland, Challenges and advances in computational docking: 2009 in review, Journal of Molecular Recognition
Zhang, Lin, Sun, Curth, Drosten et al., Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors, Science
Zhang, Mylonakis, In inpatients with COVID-19, none of remdesivir, hydroxychloroquine, lopinavir, or interferon β-1a differed from standard care for in-hospital mortality, Annals of internal medicine
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:p>In the present study, we have described how by using molecular docking and molecular dynamics (MD) simulation studies the combination drug of ivermectin and doxycycline can be used as a potential inhibitor for Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) virus. In lieu of unavailability of specific cure of coronavirus disease of 2019 (COVID-19) till now various possibilities for individual and combination drugs have been explored by the medical practitioners/scientists for the remedial purpose of CoV-2 infections. 3C-like protease (3CL<jats:sup>pro</jats:sup>) is the main protease of SARS-CoV-2 virus which plays an essential role in mediating viral replication in the human body. 3CL<jats:sup>pro</jats:sup> protein can serve as an attractive drug target. In this work, we have studied drug: 3CL<jats:sup>pro</jats:sup> interactions by <jats:italic>in-silico</jats:italic> molecular docking and MD simulation approaches. Common and easily available antiviral drugs ivermectin, doxycycline and their combination can regulate 3CL<jats:sup>pro</jats:sup> protein's function due to its easy inhibition.</jats:p>",
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