In Silico study for acyclovir, ganciclovir and its derivatives to fight the COVID-19: Molecular docking, DFT calculations, ADME and td-Molecular dynamics simulations

In the present work, we have designed acyclovir (A), ganciclovir (G) and derivative of hydroxymethyl derivative of ganciclovir (CH2OH of G, that is D) and investigated its potential against the Mpro of nCoV. Density functional theory (DFT) calculations of A, G and D were performed using Gaussian 16 on applying B3LYP under default condition to investigate the delocalization of electron density in their optimized geometry. Free energy of A, G and D were calculated in Hartree per particle. It can be seen that D has the least free energy. Further, the molecular docking of the A, G and D against the Mpro of nCoV was performed using iGemdock and the binding energy for A, G and D were calculated in kcal/mol. It can be seen the D showed effective binding, that is maximum inhibition. For a better understanding of the inhibition of the Mpro of nCoV by A, G and D, temperature dependent molecular dynamics simulations were performed. Various trajectories like RMSD, RMSF, Rg and hydrogen bond were extracted and analyzed. The results of molecular docking corroborate the MD simulations and D could be a promising candidate against Mpro of nCoV.

Interactions between main protease of SARS-CoV-2 and testosterone or progesterone using computational approach.

SARS-CoV-2 is drastically spread across the globe in a short period of time and affects the lives of billions. There is a need to find the promising drugs like candidates against the inhibition of novel corona virus or SARS-CoV-2. Herein, the interaction on sex hormones (testosterone and progesterone) with Mpro of SARS-CoV-2 was investigated with the help of molecular docking. The binding energy for the formation complex between the progesterone and testosterone with main protease of SARS-CoV-2 are -86.05 and -91.84 kcal/mol, respectively. From this, it can be understood that testosterone showed better binding affinity with Mpro of nCoV and thus, more inhibition of the main protease. Then, the binding was further studied using molecular dynamics simulations at different temperatures (300, 310 and 325) K. It has been observed that the formations of complex between the Mpro of nCoV with testosterone/ progesterone is better at 300 K than 310 and 325 K. Further, it is found that the more effective binding of testosterone with Mpro of nCoV is observed than the progesterone based on the RMSD, RMSF and H-bond trajectories. Results indicate the promising nature of testosterone towards the inhibition of Mpro of nCoV.

L-amino-acids as immunity booster against COVID-19: DFT, molecular docking and MD simulations.

There is great interest to explore the importance of different amino-acids on immunity of human. Immunity helps to protect us from the pathogenic infections. The amino-acids are being use to give energy and is also used as an important basic molecule for the making of cells, protecting cell and others. Still, a little information is known for their importance in the inhibition of main protease of SARS-CoV-2. As known, tens of billions of humans are infected due to the SARS-CoV-2 and about a million of deaths are reported due to it or COVID. As of now, no promising drug is available in the market to cure the patients from this infection. Even, the medicines beings used for the partial cure may have some side effects. Therefore, the focus is to explore the natural amino-acids against the Mpro of SARS-CoV-2 as using of amino-acids is not toxic to humans. In the present work, authors have studied the amino-acids using DFT calculations and then they were explored for their promising role in the inhibition of main protease of SARS-CoV-2 using molecular docking and molecular dynamics simulations. Out of the 20 amino-acids, arginine found to best against the main protease of SARS-CoV-2 using the molecular docking and the binding energy was -0.94 kcal/ mol. Further, molecular dynamics simulations for the main protease of SARS-CoV-2 with and without arginine was performed using the Amber and different thermodynamic parameters like ΔH and TΔS to get ΔG, comes out to be 2.74 kcal/mol. It is expected that arginine can boost the immunity.

Investigate the interaction of testosterone/progesterone with ionic liquids on varying the anion to combat COVID-19: Density functional theory calculations and molecular docking approach.

Hormones like testosterone and progesterone in the humans play significant role in the regulation of various biological processes like the body growth, reproduction, and others. In last two decades, researchers are using ionic liquids (ILs) extensively in different areas of sciences, and they are a novel class of compounds as well as their polarity can be tuned. ILs are multidisciplinary in nature and can be used in chemistry, materials science, chemical engineering, and environmental science. Further, ILs are being explored to increase the solubility of drugs or biological potential molecules. Testosterone and progesterone are found to be not very polar in nature; therefore, the authors attempt to increase the solubility of testosterone and progesterone via interaction with ILs. It was studied with density functional theory calculations using Gaussian, and an increase in the value of dipole moment is observed for the complex of testosterone/progesterone with the ILs in comparison of individual one. The optimization energy and other thermodynamic energies of the ILs (IL1-IL3), testosterone (T), testosterone-IL (T-IL1 to T-IL3), progesterone (P), and progesterone-ILs (P-IL1 to P-IL3) are found to be negative. Further, the change in free energy for the formation of complexes at room temperature is calculated. Further, the authors have investigated the synergistic effect of testosterone and progesterone against the main protease of new coronavirus using molecular docking. It is observed that the testosterone-IL1 {IL1-3-(2-hydroxyethyl)-1-methyl-1H-imidazol-3-ium 2,4,6-trinitrophenolate} is found to be prominent against the main protease of SARS-CoV-2.

Structurally modified compounds of hydroxychloroquine, remdesivir and tetrahydrocannabinol against main protease of SARS-CoV-2, a possible hope for COVID-19: Docking and molecular dynamics simulation studies.

Now a days, more than 200 countries faces the health crisis due to epidemiological disease COVID-19 caused by SARS-CoV-2 virus. It will cause a very high impact on world's economy and global health sector. Earlier the structure of main protease (Mpro) protein was deposited in the RCSB protein repository. Hydroxychloroquine (HCQ) and remdesivir were found to effective in treatment of COVID-19 patients. Here we have performed docking and molecule dynamic (MD) simulation study of HCQ and remdesivir with Mpro protein which gave promising results to inhibit Mpro protein in SARS-CoV-2. On the basis of results obtained we designed structurally modified 18 novel derivatives of HCQ, remdesivir and tetrahydrocannabinol (THC) and carried out docking studies of all the derivatives. From the docking studies six molecules DK4, DK7, DK10, DK16, DK17 and DK19 gave promising results and can be use as inhibitor for Mpro of SARS-CoV-2 to control COVID-19 very effectively. Further, molecular dynamics simulation of one derivative of HCQ and one derivative of tetrahydrocannabinol showing excellent docking score was performed along with the respective parent molecules. The two derivatives gave excellent docking score and higher stability than the parent molecule as validated with molecular dynamics (MD) simulation for the binding affinities towards Mpro of SARS-CoV-2 thus represented as strong inhibitors at very low concentration.

Xanthene based hybrid analogues to inhibit protease of novel corona Virus: Molecular docking and ADMET studies.

In December 2019, the SARS-CoV-2 was reported for the first time and the infected person is reported at Wuhan, China. Till date, about twenty four million people around the world are infected due to the SARS-CoV-2. The structure of this corona virus is new and different from other corona viruses. The genome has a positive sense single RNA strand and it is responsible for the encoding of the protein. The protease of the SARS-CoV-2 is responsible for the cleavage and therefore, it should be targeted to develop medicine. Till date, no medicine or vaccine is in the market to cure from the infection. Researchers around the world are working on the development of efficacious and safe vaccine/ drug to cure from the infection. Therefore, the authors used previously synthesized compounds, xanthene-triazole-chloroquinoline/ xanthene-chloroquinoline hybrids for the inhibition of the main protease of the SARS-CoV-2 via using computational tools, molecular docking and ADMET properties. COMD AP3 was found to be the best candidate from the library of the designed molecules. It has acceptable solubility along with the distribution and metabolism property. ADMET results corroborate the docking result towards the potency of COMP AP3.