Investigation of Some Antiviral N-Heterocycles as COVID 19 Drug: Molecular Docking and DFT Calculations

The novel coronavirus, COVID-19, caused by SARS-CoV-2, is a global health pandemic that started in December 2019. The effective drug target among coronaviruses is the main protease Mpro, because of its essential role in processing the polyproteins that are translated from the viral RNA. In this study, the bioactivity of some selected heterocyclic drugs named Favipiravir (1), Amodiaquine (2), 2′-Fluoro-2′-deoxycytidine (3), and Ribavirin (4) was evaluated as inhibitors and nucleotide analogues for COVID-19 using computational modeling strategies. The density functional theory (DFT) calculations were performed to estimate the thermal parameters, dipole moment, polarizability, and molecular electrostatic potential of the present drugs; additionally, Mulliken atomic charges of the drugs as well as the chemical reactivity descriptors were investigated. The nominated drugs were docked on SARS-CoV-2 main protease (PDB: 6LU7) to evaluate the binding affinity of these drugs. Besides, the computations data of DFT the docking simulation studies was predicted that the Amodiaquine (2) has the least binding energy (−7.77 Kcal/mol) and might serve as a good inhibitor to SARS-CoV-2 comparable with the approved medicines, hydroxychloroquine, and remdesivir which have binding affinity −6.06 and −4.96 Kcal/mol, respectively. The high binding affinity of 2 was attributed to the presence of three hydrogen bonds along with different hydrophobic interactions between the drug and the critical amino acids residues of the receptor. Finally, the estimated molecular electrostatic potential results by DFT were used to illustrate the molecular docking findings. The DFT calculations showed that drug 2 has the highest of lying HOMO, electrophilicity index, basicity, and dipole moment. All these parameters could share with different extent to significantly affect the binding affinity of these drugs with the active protein sites.

[1]  Wu Zhong,et al.  Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro , 2020, Cell Discovery.

[2]  P. Glue,et al.  The clinical pharmacology of ribavirin. , 1999, Seminars in liver disease.

[3]  Cheng‐He Zhou,et al.  Heterocyclic Naphthalimides as New Skeleton Structure of Compounds with Increasingly Expanding Relational Medicinal Applications. , 2016, Current topics in medicinal chemistry.

[4]  William A. Lee,et al.  Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys , 2016, Nature.

[5]  H. Ji,et al.  Bi-directional differentiation of single bronchioalveolar stem cells during lung repair , 2020, Cell Discovery.

[6]  S. Periandy,et al.  NBO, conformational, NLO, HOMO-LUMO, NMR and electronic spectral study on 1-phenyl-1-propanol by quantum computational methods. , 2015, Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy.

[7]  K. Chaieb,et al.  N-alkyl 2-pyridone versus O-alkyl 2-pyridol: Ultrasonic synthesis, DFT, docking studies and their antimicrobial evaluation , 2020 .

[8]  Xu Liu,et al.  In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[9]  T. Pal,et al.  DFT investigations of linear Zn3-type complex with compartmental N/O-donor Schiff base: Synthesis, characterizations, crystal structure, fluorescence and molecular docking , 2020 .

[10]  M. Uzzaman,et al.  Physiochemical, molecular docking, and pharmacokinetic studies of Naproxen and its modified derivatives based on DFT , 2018, International Journal of Scientific Research and Management.

[11]  J. Hay,et al.  The effect of 2'-fluoro-2'-deoxycytidine on herpes virus growth. , 1985, Biochimica et biophysica acta.

[12]  S. Parveen,et al.  Computational and molecular docking approaches of a New axially chiral BODIPY fluorescent dye , 2020 .

[13]  S. Parveen,et al.  A new chiral boron-dipyrromethene (BODIPY)-based fluorescent probe: molecular docking, DFT, antibacterial and antioxidant approaches , 2019, Journal of biomolecular structure & dynamics.

[14]  D. Smee,et al.  Favipiravir (T-705), a novel viral RNA polymerase inhibitor. , 2013, Antiviral research.

[15]  H. Ghabbour,et al.  Spectroscopic identification, structural features, Hirshfeld surface analysis and molecular docking studies on stiripentol: An orphan antiepileptic drug , 2019, Journal of Molecular Structure.

[16]  R. Shetty,et al.  Therapeutic opportunities to manage COVID-19/SARS-CoV-2 infection: Present and future , 2020, Indian journal of ophthalmology.

[17]  D. Hangauer,et al.  Modulating hydrogen-bond basicity within the context of protein-ligand binding: A case study with thrombin inhibitors that reveals a dominating role for desolvation. , 2017, European journal of medicinal chemistry.

[18]  M. M. Hoque,et al.  Molecular Recognition of Azelaic Acid and Related Molecules with DNA Polymerase I Investigated by Molecular Modeling Calculations , 2016, Interdisciplinary Sciences: Computational Life Sciences.

[19]  N. Kurita,et al.  Specific interactions between tau protein and curcumin derivatives: Molecular docking and ab initio molecular orbital simulations. , 2020, Journal of molecular graphics & modelling.

[20]  R. Baric,et al.  Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV , 2020, Nature Communications.

[21]  F. Cheng,et al.  Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2 , 2020, Cell Discovery.

[22]  Xiliang Wang,et al.  COVID-19: a new challenge for human beings , 2020, Cellular & Molecular Immunology.

[23]  Kai Zhao,et al.  A pneumonia outbreak associated with a new coronavirus of probable bat origin , 2020, Nature.

[24]  R. Nussinov,et al.  Computational network biology: Data, models, and applications , 2020 .

[25]  Shiew-Mei Huang,et al.  Physiologically Based Pharmacokinetic Modeling in Regulatory Science: An Update From the U.S. Food and Drug Administration's Office of Clinical Pharmacology. , 2019, Journal of pharmaceutical sciences.

[26]  N. Linton,et al.  Serial interval of novel coronavirus (COVID-19) infections , 2020, International Journal of Infectious Diseases.

[27]  G. Gao,et al.  A Novel Coronavirus from Patients with Pneumonia in China, 2019 , 2020, The New England journal of medicine.

[28]  Andrzej Kloczkowski,et al.  Role of Resultant Dipole Moment in Mechanical Dissociation of Biological Complexes , 2018, Molecules.

[29]  Sheng-Yong Yang,et al.  Individualized network-based drug repositioning infrastructure for precision oncology in the panomics era , 2016, Briefings Bioinform..

[30]  S. Tang,et al.  COVID-19: An Update on the Epidemiological, Clinical, Preventive and Therapeutic Evidence and Guidelines of Integrative Chinese-Western Medicine for the Management of 2019 Novel Coronavirus Disease. , 2020, The American journal of Chinese medicine.

[31]  Yunhui Liu,et al.  Potential interventions for novel coronavirus in China: A systematic review , 2020, Journal of medical virology.

[32]  Cynthia Liu,et al.  Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases , 2020, ACS central science.

[33]  Feixiong Cheng,et al.  In Silico Oncology Drug Repositioning and Polypharmacology. , 2018, Methods in molecular biology.

[34]  R. Rubbiani,et al.  N-Heterocyclic carbene metal complexes in medicinal chemistry. , 2013, Dalton transactions.

[35]  M. L. Serrano,et al.  Unrevealing sequence and structural features of novel coronavirus using in silico approaches: The main protease as molecular target , 2020, EXCLI journal.

[36]  David S. Goodsell,et al.  AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility , 2009, J. Comput. Chem..

[37]  F. Cheng,et al.  Drug Repurposing: New Treatments for Zika Virus Infection? , 2016, Trends in molecular medicine.

[38]  P. Lekcharoensuk,et al.  In silico and in vitro analysis of small molecules and natural compounds targeting the 3CL protease of feline infectious peritonitis virus , 2019, Antiviral Research.

[39]  Ning Zhu,et al.  Emerging Understanding of Etiology and Epidemiology of the Novel Coronavirus (COVID-19) infection in Wuhan, China , 2020 .

[40]  P. Garner,et al.  Systematic review of amodiaquine treatment in uncomplicated malaria , 1996, The Lancet.

[41]  Wu Zhong,et al.  Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro , 2020, Cell Research.

[42]  D. Raoult,et al.  New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? , 2020, International Journal of Antimicrobial Agents.

[43]  Jerry Avorn,et al.  The $2.6 billion pill--methodologic and policy considerations. , 2015, The New England journal of medicine.