key: cord-0751574-kin0fom5 authors: Hussein, R.K.; Elkhair, H.M. title: Molecular Docking Identification for the efficacy of Some Zinc Complexes with Chloroquine and Hydroxychloroquine against Main Protease of COVID-19 date: 2021-01-25 journal: J Mol Struct DOI: 10.1016/j.molstruc.2021.129979 sha: 756da96af989eac613e09286a5f055d57ebc10a4 doc_id: 751574 cord_uid: kin0fom5 Vast amount of research has been recently conducted to discover drugs for efficacious treatment of corona virus disease 2019 (COVID-19). The ambiguity about using Chloroquine/ Hydroxychloroquine to treat this illness was a springboard towards new methods for improving the adequacy of these drugs. The effective treatment of COVID-19 using Zinc complexes as add-on to Chloroquine/ Hydroxychloroquine has received major attention in this context. The current studies have shed a light on molecular docking and molecular dynamics methodologies as powerful techniques in establishing therapeutic strategies to combat COVID-19 pandemic. We are proposing some zinc compounds coordination to Chloroquine/ Hydroxychloroquine in order to enhance their activity. The molecular docking calculations showed that Zn(QC)Cl2(H2O) has the least binding energy -7.70 Kcal /mol then Zn(HQC)Cl2(H2O) -7.54 Kcal /mol. The recorded hydrogen bonds were recognized in the strongest range of H Bond category distances. Identification of binding site interactions revealed that the interaction of Zn(QC)Cl2(H2O)with the protease of COVID-19 results in three hydrogen bonds, while Zn(HQC)Cl2(H2O) exhibited a strong binding to the main protease receptor by forming eight hydrogen bonds. The dynamic behavior of the proposed complexes was revealed by molecular dynamics simulations. The outcomes obtained from Molecular dynamics calculations approved the stability of Mpro-Zn(CQ/HCQ)Cl2H2O systems. These findings recommend Zn (CQ) Cl2H2O and Zn (HCQ) Cl2H2O as potential inhibitors for COVID-19 Mpro. The crisis has motivated researchers from different fields of sciences towards vaccine finding against this novel disease. For many years, Chloroquine (CQ) was reported as a potential remedy to alleviate exacerbation of pneumonia. Also CQ has a capability of inhibition of autophagy and motivating the apoptosis in malignant cells in broad experimental models [2] [3] [4] [5] . These positive effects nominated CQ to be tested in the treatment of COVID-19 infection [6] [7] [8] . Hydroxychloroquine (HCQ) was first prescribed as anti-malaria drug and it was prove of being useful to treat other diseases such as lupus erythematosus, rheumatoid arthritis. Recently HCQ has been proposed for COVID-19 treatment according to the protocols published during 2020 [9] [10] [11] [12] . The proven acknowledge for the efficiency of CQ/HCQ treatment for COVID-19 is still questioned and lacking for experimental evidence. Various attempts have been made to improve the therapeutic use for CQ/HCQ including metal complexes addition [13, 14] . Zinc element has antiviral effect and could be used to reduce the viral activities of COVID-19. Philip Carlucci et al suggested using zinc sulfate as add-on therapy to HCQ against COVID-19 [15] . Clinical trials have been made to demonstrate that the improvement of the efficacy of CQ/HCQ against COVID-19 may require Zinc additives [16] . Derwand et al hypothesized that CQ/HCQ plus zinc supplementation may be more effective in reducing COVID-19 morbidity and mortality than CQ or HCQ in monotherapy [17] . There was a shortage in most of those studies in identifying the synthesis and characterization of CQ/HCQ-zinc complexes. The availability of the chemical and molecular structure of zinc combined to CQ/HCQ may enrich the drug design field in the framework of increasing the potency of CQ/HCQ against COVID-19. Molecular docking is one of the best techniques in the scientific community for rational design of drugs. Docking addresses the binding between drugs and protein via active sites determination. Molecular dynamics simulations are used in virtual screening the dynamic behavior of protein or protein-molecules complexes. Molecular docking and molecular dynamics aided in understanding the molecular function and biological process of drugs, both have been used extensively in recent time to find an effective vaccine for COVID-19. [18] [19] [20] [21] In this article, the development of the therapeutic activities of CQ/HCQ against COVID-19 has been based on the incorporation of CQ/HCQ with some zinc structures. The stability of the proposed structures was assessed by molecular dynamic simulations. Molecular docking calculations were carried out to calculate the binding energies and site interactions for inhibition capability evaluation of COVID-19 main protease. The optimum structures of all compounds are illustrated in Figure 1 . CQ and HCQ serve a wide variety of in-vitro activity against viruses and used extensively as antimalarial drugs [22, 23] . In 1937, Andersag, Breitner and Jung had synthesized CQ for the first time [24] . HCQ is prepared by substitution the N-diethyl group side chain of CQ by N-hydroxy-ethyl side chain [25, 26] . The zinc complexes bind to the similar structure of CQ and HCQ through unsubstituted Many studies showed that Mpro (PDB ID 6LU7) the main protease of COVID-19 is the key for its viral replication. This makes it a potent target for potential inhibitor drugs [29, 30] . The crystal structure of 6lu7 Mpro was downloaded from Protein Data Bank (PDB: https://www.rcsb.org). The chemical structure of CQ (CID: 2719), HCQ (CID: 3652) were taken from PUBCHEM database. The studied ligands were drawn in the Avogadro molecule editor, and then their stable NAnoscale Molecular Dynamics (NAMD) software was used to perform Molecular dynamics simulations [33] . Simulation parameterization specified in topologies and parameter files of ligands and proteins were prepared using the CHARMM-GUI [34] . The CHARMM36 force field was used to parameterize the system which was solvated in TIP3P water solvation box and neutralized by adding sodium chloride ions. Energy-minimization was applied to system and then equilibrated for 200 ps. Subsequently, systems were simulated at constant temperature The molecular docking results are recorded in Table 1 . Illustrative figures of different orientations for the ligands interaction with protein target are included, the ligand is marked as blue stick model while the protein is displayed as a surface. The more negative binding energy bonds are a primary contributor factor in supporting the binding affinity of drugs with the receptor. Strong hydrogen bonding interaction represents a high binding capability between ligand and protein [37] . The values of binding energy and inhibition constant for CQ and HCQ are consistent with previous concerned work [38] . There were no commendable findings for The 2D binding sites diagram of CQ and HCQ with 6lu7 target is illustrated in Figure (2a, b) . CQ demonstrates an average docking by a conventional hydrogen bond with HIS164 residue at 2.31 Å, while HCQ has two hydrogen bonds interactions with MET49 and GLN189 at 1.99 and 2.17 Å respectively. In Figure (3-a, b) , Zn(CQ)Cl and Zn(HCQ)Cl showed no noteworthy improvement in binding modes than in CQ nor HCQ; Zn(CQ)Cl has one hydrogen bond with HIS 164 amino acid at 2.14 Å while the residues HIS164 and GLU166 are involved in the formation of two hydrogen bonds with Zn(HCQ)Cl at distances 3.06and 2.02 Å. This result is realistic with the very close blind docking results (mentioned in Table 1 ) between CQ and Zn(CQ)Cl or between HCQ and Zn(HCQ)Cl. Three hydrogen bonds were formed in the interaction between Zn(QC)Cl2(H2O) and Mpro as shown in Figure 4 -a (two hydrogen bonds with GLU166→ 1.76, 1.95 Å and one hydrogen bond with ARG188→2.06Å). The docking representation of the last complex has shown strong binding activity. As revealed in Figure 4 The data will be available upon request. [ Dual inhibition of autophagy and the AKT pathway in prostate cancer Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis Autophagy Inhibitor Chloroquine Enhanced the Cell Death Inducing Effect of the Flavonoid Luteolin in Metastatic Squamous Cell Carcinoma Cells Chloroquine for COVID-19: rationale, facts, hopes Therapeutic use of chloroquine and hydroxychloroquine in COVID-19 and other viral infections: A narrative review Chloroquine as a Potential Treatment and Prevention Measure for the 2019 Novel Coronavirus: A Review Optimizing the Use of Hydroxychloroquine in the Management Given Its Pharmacological Profile Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19 COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression Hydroxychloroquine for the management of COVID-19: Hope or Hype? A Systematic review of the current evidence Metalchloroquine derivatives as possible anti-malarial drugs: evaluation of anti-malarial activity and mode of action Structural and some medicinal characteristics of the copper(II)-hydroxychloroquine complex Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients Improving the efficacy of chloroquine and hydroxychloroquine against SARS-CoV-2 may require zinc additives -A better synergy for future COVID-19 clinical trials Does zinc supplementation enhance the clinical efficacy of chloroquine/hydroxychloroquine to win today's battle against COVID-19? Protein structure-based drug design: from docking to molecular dynamics Inhibitory activity of hydroxychloroquine on COVID-19 main protease: An insight from MD-simulation studies COVID-19: Immunology and treatment options ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases Antimalarials -are they effective and safe in rheumatic diseases? Process for the preparation of quinoline compounds containing amino groups with basic substituents in the 4-position Chemistry of clinically active anti-inflammatory compounds Influence of hydroxychloroquine on the bioavailability of oral metoprolol Synthesis, Characterization and Crystal Structure of a Polymeric Zinc(II) Complex Containing the Antimalarial Quinine as Ligand Synthesis and characterization of new copper-and zinc-chloroquine complexes and their activities on respiratory burst of polymorphonuclear leukocytes Lopinavir; A Potent Drug against Coronavirus Infection: Insight from Molecular Docking Study Designing of improved drugs for COVID-19: Crystal structure of SARS-CoV-2 main protease Mpro AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility Scalable molecular dynamics with NAMD Simulations Using the CHARMM36 Additive Force Field VMD: Visual molecular dynamics Automated Docking Screens: A Feasibility Study Binding Affinity via Docking: Fact and Fiction The Molecular Docking Study of Potential Drug Candidates Showing Anti-COVID-19 Activity by Exploring of Therapeutic Targets of SARS-CoV-2 An introduction to hydrogen bonding