key: cord-0683894-pgogiflc authors: Mhatre, Susmit; Gurav, Nitisha; Shah, Mansi; Patravale, Vandana title: Entry-inhibitory role of catechins against SARS-CoV-2 and its UK variant date: 2021-06-10 journal: Comput Biol Med DOI: 10.1016/j.compbiomed.2021.104560 sha: 580e92c45ffc315c360159b9fe1dabae118e70ea doc_id: 683894 cord_uid: pgogiflc BACKGROUND: The global pandemic caused by an RNA virus capable of infecting humans and animals, has resulted in millions of deaths worldwide. Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infects the lungs and the gastrointestinal tract to some extent. Rapid structural mutations have increased the virulence and infectivity of the virus drastically. One such mutated strain known as the UK variant has caused many deaths in the United Kingdom. HYPOTHESIS: Among several indigenous natural ingredients used for prevention and cure of many diseases, the catechins have been reported for their antiviral activity, even against SARS-CoV-2. Characteristic mutations present on the spike protein have presented the newer strain its enhanced infectivity. The spike protein helps the virus bind to ACE2 receptor of the host cell and hence is a drug target. Catechins have been reported for their entry-inhibitory activity against several viruses. METHOD: In this study, we performed molecular docking of different catechins with the wild and mutant variants of the spike protein of SARS-CoV-2. The stability of the best docked complexes was validated using molecular dynamics simulation. RESULTS: The in-silico studies show that the catechins form favourable interactions with the spike protein and can potentially impair its function. Epigallocatechin gallate (EGCG) showed the best binding among the catechins against both the strains. Both the protein-ligand complexes were stable throughout the simulation time frame. CONCLUSION: The outcomes should encourage further exploration of the antiviral activity of EGCG against SARS-CoV-2 and its variants. Environment (MOE) software on a Windows 10 system. Two docked complexes, 160 EGCG and wild spike glycoprotein complex and the EGCG and mutated spike 161 glycoprotein, were simulated. The first step was to add a solvent box around the 162 protein-ligand complex to represent a biological system. A water box of appropriate 163 length to soak entire complex was added using the Water Soak module of MOE. The 164 complexes were then protonated at a pH of 7.4 at a temperature of 298 K. All the atoms 165 of the complex were typed with the AMBER99 forcefield. Next, the complex was 166 minimized to get a stable conformation. Finally, the MD simulation was performed. The 167 complex was heated at a temperature of 310 K from an initial temperature of 300 K for 168 J o u r n a l P r e -p r o o f a period of 100 ps in a NVT ensemble at a pressure of 101 kPA. The complex was then 169 simulated for a period of 20 ns at a temperature of 310 K at same pressure in NVT 170 ensemble. Lastly, the complex was cooled down to a temperature of 300 K for a time 171 period of 100 ps. The trajectory generated was analysed by plotting the energy changes 172 through the timesteps. amino acid residue present in the active binding site was THR716 which mutated to 208 ILE716. This mutation increased the protein energy and thus decreased the stability. 209 However, this change was very small considering the overall protein energy. The 210 significant change that these mutations produce was accounted to the conformation of 211 the active binding site and the types of interactions allowed with the ligand. Considering 212 all the mutations on the protein, the overall stability was negligibly affected. The change 213 in conformation altered the interactions which may alter the binding mode as well as the 214 docking score. Figure 2 represents the change in orientation of the protein change as 215 (Table 1 here in screening drug candidates. In this study, we used molecular docking to screen the 241 activity of the catechins against the spike protein of both the wild and mutated strains of 242 SARS-CoV-2. Table 2 represents the docking scores of the catechins. 243 (Table 2 here The docking scores of all the catechins were better than that of NAG, indicating that the 247 catechins have a higher affinity to bind to the spike proteins than the native ligand. 248 Thus, these molecules can selectively bind to the active site over NAG. The interactions 249 between catechins and the amino acids of the active binding site form a stronger 250 complex than that with NAG. These interactions are represented in figures 3 and 4. 251 EGCG had better docking scores among the others, although the difference was not 252 significant. This is in agreement with previous reports [31, 43] . The same trend is 253 followed for wild and mutated strains. The difference between the docking scores for 254 the two strains for almost all the catechins is small. Hence, the scores of the catechins 255 indicating that the protein-ligand complexes are stable throughout the simulation 305 process. 306 (Table 3 here) 307 (Table 4 here and side-effects. The maximum tolerance of EGCG is much higher than many antiviral 340 drugs owing to its natural origin and low acute as well as chronic toxicity values. 341 Hence, the formulations involving EGCG can support high dosages to ensure the 342 required bioavailability. Other approaches that have been successfully studied to 343 improve the oral bioavailability of EGCG include structure modification and nano 344 delivery through nanoparticles, nanoliposomes, double emulsions, and nanoemulsions 345 [48]. 346 (Table 5 here) 347 The COVID-19 global pandemic has proved that the fields of science and medicine are 349 much equipped than before to deal with a disease outbreak, but there is a need for more Catechin -5.7 -5.7 Catechin Gallate -5.8 -6.5 Epicatechin -5.7 -6.0 Gallocatechin -5.8 -5.9 Epigallocatechin -5.9 -5.7 Epicatechin Gallate -6.1 -6.1 Gallocatechin Gallate -5.9 -6.3 The UK variant of SARS-CoV-2 has caused a sudden increase in the number of 639 COVID-19 cases. Characteristic point mutations present on the spike protein have made 640 this new strain far more infectious than the wild strain. 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