An investigation for the interaction of gamma oryzanol with the Mpro of SARS-CoV-2 to combat COVID-19: DFT, molecular docking, ADME and molecular dynamics simulations.

COVID-19 has affected more or less every nation across the world and affected the economy very badly. Infection of this virus in human took the life of millions. We have already faced the first and the second waves of COVID-19 and recently, the nations or humanity is afraid of new strain, that is, OMICRON. Considered to highly infectious than the previous strains. Therefore, the researchers are working to find a promising molecule with no or permissible toxicity. In the present work, authors have chosen 10 molecules including the molecules used in curing the infection from nCoV. All the molecules were docked against Mpro of nCoV using iGemdock, a reliable computational tool. Based on the binding energy obtained, it can be seen that only latermovir; remdesivir; zanamivir showed better binding affinity than the gamma oryzanol, the molecule of interest in this work. These three molecules are already in use to cure the patients siffering from the infection of nCoV. But, we need a cost effective and easily available molecule to fight against this viral infection. The binding energy obtained for the formation of complex of gamma oryzanol with Mpro of nCoV through molecular docking is -118.787 kcal/mol. It forms conventional hydrogen bonds with the CYS145 (2.51 Å), LEU141 (3.01 Å) and SER144 (3.09 Å); forms C-H bonds with PHE140 (3.37 Å) and HIS163 (2.91 Å), forms alkyl interactions with ALA191 (3.59 and 4.74 Å), CYS145 (4.90 Å). One interesting information is obtained that the value of log Kp of gamma oryzanol is least means more permeable to skin in comparison of other molecules used in the work. Gamma oryzanol in known for to its biological potency like it can modulate the oxidative stress as well as inflammation. DFT calculations of gamma oryzanol (GO) was made at different temperature and no change in the delocalization of electron density as well no change in free energy is observed. Molecular dynamics (MD) simulations of gamma oryzanol with the Mpro of nCoV at different temperatures was performed. The formation of the complex between GO and Mpro of CoV at 290 K, 300 K, 310 K and 320 K for 100 ns was investigated. It has been observed that the effective binding is observed at 290 K, therefore, it can be said that the inhibition of the Mpro of nCoV with GO is maximum at 290 K.Communicated by Ramaswamy H. Sarma.

A comparative study of 5- fluorouracil, doxorubicin, methotrexate, paclitaxel for their inhibition ability for Mpro of nCoV: Molecular docking and molecular dynamics simulations

A new corona virus (nCoV) is aetiological agent responsible for the viral pneumonia epidemic. Three is no specific therapeutic medicines available for the treatment of this condition and also effective treatment choices are few. In this work author tried to investigate some repurposing drug such as 5- fluorouracil, doxorubicin, methotrexate and paclitaxel against the main protease (Mpro) of nCoV by the computational model. Molecular docking was performed to screen out the best compound and doxorubicin was found to have minimum binding energy −121.89 kcal/mol. To further study, MD simulations were performed at 300 K and the result successfully corroborate the energy obtained by molecular docking. Temperature dependent MD simulation of the best molecule that is doxorubicin obtained from docking result was performed to check the variation in structural changes in Mpro of nCoV at 290 K, 310 K, 320 K and 325 K. It is sound that doxorubicin binds effectively with Mpro of nCoV at 290 K. Further ADME properties of the 5- fluorouracil, doxorubicin, methotrexate and paclitaxel were also evaluated to understand the bioavailability.

In Silico Evaluation of Binding of 2-Deoxy-D-Glucose with Mpro of nCoV to Combat COVID-19.

COVID-19 has threatened the existence of humanity andthis infection occurs due to SARS-CoV-2 or novel coronavirus, was first reported in Wuhan, China. Therefore, there is a need to find a promising drug to cure the people suffering from the infection. The second wave of this viral infection was shaking the world in the first half of 2021. Drugs Controllers of India has allowed the emergency use of 2-deoxy-D-glucose (2DG) in 2021 for patients suffering from this viral infection. The potentiality of 2-deoxy-D-glucose to intervene in D-glucose metabolism exists and energy deprivation is an effective parameter to inhibit cancer cell development. Once 2DG arrives in the cells, it becomes phosphorylated to 2-deoxy-D-glucose-6-phosphate (2-DG6P), a charged molecule expressively captured inside the cells. On the other hand, 2DG lacks the ability to convert into fructose-6-phosphate, resulting in a hampering of the activity of both glucose-6-phosphate isomerase and hexokinase, and finally causing cell death. Hence, the potential and effectiveness of 2DG with the main protease (Mpro) of novel coronavirus (nCoV) should be investigated using the molecular docking and molecular dynamics (MD) simulations. The ability of 2DG to inhibit the Mpro of nCoV is compared with 2-deoxyglucose (2DAG), an acyclic molecule, and 2-deoxy-D-ribose (2DR). The binding energy of the molecules with the Mpro of nCoV is calculated using molecular docking and superimposed analysis data is obtained. The binding energy of 2DG, 2DR and 2DAG was -2.40, -2.22 and -2.88 kcal/mol respectively. Although the molecular docking does not provide reliable information, therefore, the binding affinity can be confirmed by molecular dynamics simulations. Various trajectories such as Rg, RMSD, RMSF, and hydrogen bonds are obtained from the molecular dynamics (MD) simulations. 2DG was found to be a better inhibitor than the 2DAG and 2DR based on the results obtained from the MD simulations at 300 K. Furthermore, temperature-dependent MD simulations of the Mpro of nCoV with promising 2DG was performed at 295, 310 and 315 K, and the effective binding with the Mpro of nCoV occurred at 295 K. With the use of DFT calculations, optimized geometry and localization of electron density of the frontier molecular orbitals were calculated.

Hunting the main protease of SARS-CoV-2 by plitidepsin: Molecular docking and temperature-dependent molecular dynamics simulations.

COVID-19 has shaken all the countries across the globe and researchers are trying to find promising antiviral to cure the patients suffering from infection and can decrease the death. Even, different nations are using repurposing drugs to cure the symptoms and these repurposing drugs are hydroxychloroquine, remdesivir, and lopinavir, and recently, India has recently given the approval for the 2-deoxy-D-glucose for emergency purpose to cure the patients suffering from the COVID-19. Plitidepsin is a popular molecule and can be used in treatment of myeloma. Plitidepsin was explored by scientists experimentally against the COVID-19 and was given to the patient. It is found to be more a promising repurposing drug against the COVID-19 than the remdesivir. Therefore, there is a need to understand the interaction of plitidepsin with the main protease of SARS-CoV-2. Molecular docking of the plitidepsin against Mpro of SARS-CoV-2 was performed and the binding energy was found to be - 137.992 kcal/mol. Furthermore, authors have performed the molecular dynamics simulations of the main protease of SARS-CoV-2 in presence of plitidepsin at 300 and 325 K. It was found that the plitidepsin binds effectively with the main protease of SARS-CoV-2 at 300 K.

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.

Promising inhibitors of main protease of novel corona virus to prevent the spread of COVID-19 using docking and molecular dynamics simulation.

Coronavirus disease-2019 (COVID-19) is a global health emergency and the matter of serious concern, which has been declared a pandemic by WHO. Till date, no potential medicine/ drug is available to cure the infected persons from SARS-CoV-2. This deadly virus is named as novel 2019-nCoV coronavirus and caused coronavirus disease, that is, COVID-19. The first case of SARS-CoV-2 infection in human was confirmed in the Wuhan city of the China. COVID-19 is an infectious disease and spread from man to man as well as surface to man . In the present work, in silico approach was followed to find potential molecule to control this infection. Authors have screened more than one million molecules available in the ZINC database and taken the best two compounds based on binding energy score. These lead molecules were further studied through docking against the main protease of SARS-CoV-2. Then, molecular dynamics simulations of the main protease with and without screened compounds were performed at room temperature to determine the thermodynamic parameters to understand the inhibition. Further, molecular dynamics simulations at different temperatures were performed to understand the efficiency of the inhibition of the main protease in the presence of the screened compounds. Change in energy for the formation of the complexes between the main protease of novel coronavirus and ZINC20601870 as well ZINC00793735 at room temperature was determined on applying MM-GBSA calculations. Docking and molecular dynamics simulations showed their antiviral potential and may inhibit viral replication experimentally. Communicated by Ramaswamy H. Sarma.