key: cord-1050232-e7p60y7c
authors: Kodchakorn, Kanchanok; Poovorawan, Yong; Suwannakarn, Kamol; Kongtawelert, Prachya
title: Molecular Modelling Investigation for Drugs and Nutraceuticals against Protease of SARS-CoV-2
date: 2020-08-18
journal: J Mol Graph Model
DOI: 10.1016/j.jmgm.2020.107717
sha: c594ad6abca6c373c661930b1a7bc1d87596a906
doc_id: 1050232
cord_uid: e7p60y7c

The widespread problem of a 2019-novel coronavirus (SARS-CoV-2) strain outbreak in Wuhan, China has prompted a search for new drugs to protect against and treat this disease. It is necessary to immediately investigate this due to the mutation of the viral genome and there being no current protective vaccines or therapeutic drugs. Molecular modelling and molecular docking based on in silico screening strategies were employed to determine the potential activities of seven HIV protease (HIV-PR) inhibitors, two flu drugs, and eight natural compounds. The computational approach was carried out to discover the structural modes with a high binding affinity for these drugs on the homology structure of the Wuhan coronavirus protease (SARS-CoV-2 PR). From the theoretical calculations, all the drugs and natural compounds demonstrated various favourable binding affinities. An interesting finding was that the natural compounds tested had a higher potential binding activity with the pocket sites of SARS-CoV-2 PR compared to the groups of HIV-PR inhibitors. The binding modes of each complex illustrated between the drugs and compounds interacted with the functional group of amino acids in the binding pocket via hydrophilic, hydrophobic, and hydrogen bond interactions using the molecular dynamics simulation technique. This result supports the idea that existing protease inhibitors and natural compounds could be used to treat the new coronavirus. This report sought to provide fundamental knowledge as preliminary experimental data to propose an existing nutraceutical material against viral infection. Collectively, it is suggested that molecular modelling and molecular docking are suitable tools to search and screen for new drugs and natural compounds that can be used as future treatments for viral diseases.

Wuhan, China has prompted a search for new drugs to protect against and treat this disease. 28

It is necessary to immediately investigate this due to the mutation of the viral genome and 29 there being no current protective vaccines or therapeutic drugs. Molecular modelling and 30 molecular docking based on in silico screening strategies were employed to determine the 31 potential activities of seven HIV protease (HIV-PR) inhibitors, two flu drugs, and eight 32 natural compounds. The computational approach was carried out to discover the structural 33 modes with a high binding affinity for these drugs on the homology structure of the Wuhan the highest binding affinity (-8.6 kcal mol -1 ). Table 1 shows a common amino acid binding 199 pocket residues within 5 Å around the ligand that was identified to play a key role in the 200 potential activity for PR inhibition. Sesamin is able to be the most stable binder with small 201 energy differences of 1.0 kcal mol -1 compared to hesperidin. This result implies that natural 202 compounds are a potential treatment option for viral infections. The binding mode of the 203 other herbal drugs was observed to bind at the same site with slightly different amino acid 204 binding poses by the energy difference 0.1 ~ 1.9 kcal mol -1 . 205 Table 1 Binding affinity (kcal mol -1 ) and common amino acid binding pocket residue in each system by AutoDock Vina. 207

Binding affinity Common amino acid binding pocket residues within 5 Å To evaluate the binding affinity of the protein-ligand interactions, the relative binding free 234 energy values obtained from MM-PBSA protocol were calculated as listed in Table 2 . The 235 results revealed that the herbal medicines hesperidin (ΔG binding = -11.96 kcal mol -1 ) binds to 236 the SARS-CoV-2 PR protein better than sesamin (ΔG binding = -9.93 kcal mol -1 ) as well as 237 HIV-PR inhibitors lopinavir (ΔG binding = -7.56 kcal mol -1 ) and remdesivir (ΔG binding = -7.85 238 kcal mol -1 

A recent literature revealed that there is no statistically significant difference was found 250 between combining drug lopinavir/ritonavir treatment and a controlled trial to clinical 251 improvement and a viral RNA detectability in patients with serious SARS-CoV-2 infection 252

[34]. This observed data confirmed the high binding free energy of lopinavir to bind with the 253 porket site of the SARS-CoV-2 PR. 254

The low binding affinity of remdesivir was observed to interact on the protease protein, 255 which might be due to aiming for different target activity of remdesivir on the RNA-256 dependent RNA polymerase related with the low affinity energy value by docking calculation 257 ( Table 1) . The free energy of the van der Waals (vdW) interactions and non-polar parts 258 (ENPOLAR) of the solvation free energy contributes favorably to the binding where there is 259 a slight energetic difference for each binding complex, as opposed to the unfavorable contributions of electrostatic energy (EEL+EPB). Each energy term (vdW, ENPOLAR, 261 EEL+EPB) of hesperidin was found to be at least two times more favorable interaction than 262 that of the other inhibitors. It can be noted that the bioactive natural products may allow 263 better application of herbal drugs for future treatment of viral infected diseases. 264

To define the essential amino acid residues that contribute to the binding affinity, per-265 residue free energy decomposition was calculated. According to the complete genomes of coronavirus from Wuhan, the protease becomes the 357 first target for therapeutic agents against viral proliferation. Computer molecular modelling 358 and molecular docking are therefore the most suitable tools to quickly screen and confirm 359 existing and new drugs as well as nutraceuticals. 360

As our results, the molecular docking and molecular dynamics simulation techniques were 361 used to successfully investigate the potential protease inhibitor approved for viral treatment. 362

The natural compounds used as nutraceuticals could be used as co-protection and treatment 363 with these existing drugs. Although the available drugs have not been considered in any 364 pharmacological assay or biological experiment to have potential activity on the SARS-CoV-365 alternative antiviral activity [11,12]. This report provides fundamental knowledge as a 367 preliminary experiment for the consideration of further measurements and to propose an 368 existing material as a nutraceutical. Consequently, subtle differences in the theoretical 369 calculations corresponding with the SARS coronavirus experimental assay should prompt 370 further investigation. 371 372

The authors declared that there is no conflict of interest regarding the publication of this 374 manuscript. 375

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