key: cord-0752097-yozhefiz authors: Singh, Prakrity; Chauhan, Shweta Singh; Pandit, Shraddha; Sinha, Meetali; Gupta, Shristee; Gupta, Anshika; Parthasarathi, Ramakrishnan title: The dual role of phytochemicals on SARS-CoV-2 inhibition by targeting host and viral proteins date: 2021-09-08 journal: J Tradit Complement Med DOI: 10.1016/j.jtcme.2021.09.001 sha: cee1518a58bd4eb96ffe463f0bf139f83d12b9a6 doc_id: 752097 cord_uid: yozhefiz BACKGROUND: The severe acute respiratory syndrome-2019 has affected more than 190 million people around the world and caused severe crises throughout the globe. Due to rapid mutation in the viral genome, it became important to simultaneously improvise the host immunity while targeting the viral protein to reduce the severity of the infection. AIM: The current computational work focuses on multi-level rigorous screening of 47 medicinal plant-based phytochemicals for discovering effective phytochemical inhibitors against the host and viral targets. EXPERIMENTAL PROCEDURE: A total of 586 phytochemicals were analyzed in detail based on their drug-likeness, pharmacological properties, and structure-based activity against the viral proteins (Spike glycoprotein, Papain-like protease, and Main protease) and host proteins (ACE2, Importin-subunit α-5, and β-1). Phytochemicals showing higher binding affinity with the dual capacity to target both the categories of proteins were further analyzed by profiling their chemical reactivity using Density-functional theory (DFT) based quantum chemical methods. Finally, detailed molecular dynamics simulations were performed to analyze the interactions of the complexes. RESULTS AND CONCLUSION: The results revealed that the selected phytochemicals from Andrographis paniculata, Aconitum heterophyllum, Costus speciosus and Inula racemosa may have the capacity to act with prominent affinity towards the host and viral proteins. Therefore, The Combination of active phytochemicals of these plants may prove to be more beneficial and can be used for developing the potential phytotherapeutic intervention. A novel corona virus (SARS-CoV-2) has been associated with infectious respiratory disease, 28 hastily spreading in the human population 1-2 . Up to April 2021, this disease has spread in more 29 than 219 countries proving to be a global pandemic 3 . Alarmingly, the number of infected 30 patients is rising day by day. At an early stage of infection, a person is associated with a cough, 31 fever, shortness of breath, and headache which further leads to severe pneumonia. The 32 epidemiological studies have revealed that apart from the age factor, an individual's immunity is 33 also severely compromised due to this virus 4 . SARS-CoV-2 shares a similar infectious and impact the viral cycle which is dependent on the host proteins. Among the viral targets, the most common is the Spike protein which is mainly responsible for 58 the entry of corona virus into the host cell by interacting with the ACE2 receptor 15-16 . Spike 59 protein is made up of two subunits (S1 and S2) where a sequence of S1 subunit is the most 60 variable part of the SARS-CoV-2 genome. Inside the host cell, the viral genome shows the expression of PL pro and 3CL pro /M pro that are 69 responsible for the formation of various non-structural proteins and further utilize the nuclear 70 importins to enter the nucleus of the host cell 15 . ACE2, Importin subunit α-5, and Importin 71 subunit β-1 are the few major host proteins that are involved in the viral infection. Drugs like 72 J o u r n a l P r e -p r o o f Ivermectin act by targeting the Importin α/β receptor of the host to weaken the viral cycle [18] [19] . It 73 is also reported that drugs acting as allosteric modulators can decrease the strength of spike and 74 ACE2 complex that will further help in the reduction of viral incubations 20 . In this context, identifying medicinal bioactive compounds that can selectively target both virus- Among the evaluated 586 phytochemicals, 161 were found to follow the drug-likeness criteria. These phytochemicals had a molecular weight below five hundred, LogP was less than five, 170 hydrogen bond acceptors count was below ten and hydrogen bond donors' counts were under 171 five. Further, these phytochemicals were also screened for the pharmacokinetic properties such (Table 1) were showed favorable activity in these 175 parameters. The permissible limit criteria of pharmacokinetic parameters for all 24 176 phytochemicals showed that their solubility was in the range between -6.5 to 0.5, with acceptable 177 BBB limits found to be in between -3.0 to 1.2, and HIA was more than 30% with low 178 Cytochrome enzyme inhibition (Supplementary Table 2 ). Ivermectin for Importin subunit α-5 and Importin subunit β-1. All the 24 phytochemicals with 213 ACE2 target had binding energy in the range of -4.42 to -8.46 (kcal/mol) and that for the control 214 compound, it was -5.19 (kcal/mol) (Supplementary Table 4 ). Hetisinone (CID_101930090) from 215 Aconitum heterophyllum showed the highest binding energy (8.46 (kcal/mol)) among all selected 216 phytochemicals. In case of Importin subunit α-5, and Importin subunit β-1 the binding energies 217 for phytochemicals ranged between -7.22 to -2.0 (kcal/mol) and -7.95 to -4.83 (kcal/mol) for 218 their respective targets (Supplementary Tables 5 and 6 ). Control compound (Ivermectin) was 219 found to be binding more favorably with the Importin subunit α-5 and Importin subunit β-1 as 220 compared to that of the chosen phytochemical for these targets (Figure 2 ). plant Costus speciosus were found to be showed the highest binding score -8. 20 and -7.40 243 kcal/mol for PLpro and Mpro, respectively (Figure 2 (e, f)). All the screened and shortlisted phytochemicals were next optimized at their minimum energy 246 state with zero imaginary frequency ( Figure 3) and their molecular properties were computed. All the optimized compounds were found to be stable and non-planar (except disulfiram). Hydroxychloroquine (HCQ). The obtained RMSD profile (Figure 5 (a) ) showed that in case of Hetisinone, the stability of the trimerization of the Spike protein as the binding pattern was found to be similar in both the cases. 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