High-throughput virtual screening of drug databanks for potential inhibitors of SARS-CoV-2 spike glycoprotein.

COVID-19, which is caused by a novel coronavirus known as SARS-CoV-2, has spread rapidly around the world, and it has infected more than 29 million individuals as recorded on 16 September 2020. Much effort has been made to stop the virus from spreading, and there are currently no approved pharmaceutical products to treat COVID-19. Here, we apply an in silico approach to investigate more than 3800 FDA approved drugs on the viral RBD S1-ACE2 interface as a target. The compounds were investigated through flexible ligand docking, ADME property calculations and protein-ligand interaction maps. Molecular dynamics (MD) simulations were also performed on eleven compounds to study the stability and the interactions of the protein-ligand complexes. The MD simulations show that bagrosin, chidamide, ebastine, indacaterol, regorafenib, salazosulfadimidine, silodosin and tasosartan are relatively stable near the C terminal domain (CTD1) of the S1 subunit of the viral S protein. The relative MMGBSA binding energies show that silodosin has the best binding to the target. The constant velocity steered molecular dynamics (SMD) simulations show that silodosin preferentially interacts with the RBD S1 and has potential to act as an interfering compound between viral spike-host ACE2 interactions. Communicated by Ramaswamy H. Sarma.

Discovery of potent inhibitors for SARS-CoV-2's main protease by ligand-based/structure-based virtual screening, MD simulations, and binding energy calculations.

COVID-19 has caused lockdowns all over the world in early 2020, as a global pandemic. Both theoretical and experimental efforts are seeking to find an effective treatment to suppress the virus. In silico drug design can play a vital role in identifying promising drug candidates against COVID-19. Herein, we focused on the main protease of SARS-CoV-2 that has crucial biological functions in the virus. We performed a ligand-based virtual screening followed by a docking screening for testing approved drugs and bioactive compounds listed in the DrugBank and ChEMBL databases. The top 8 docking results were advanced to all-atom MD simulations to study the relative stability of the protein-ligand interactions. MD simulations support that the catalytic residue, His41, has a neutral side chain with a protonated delta position. An absolute binding energy (ΔG) of -42 kJ mol-1 for the protein-ligand (Mpro-N3) complex has been calculated using the potential-of-mean-force (geometrical) approach. Furthermore, the relative binding energies were computed for the top docking results. Our results suggest several promising approved and bioactive inhibitors of SARS-CoV-2 Mpro as follows: a bioactive compound, ChEMBL275592, which has the best MM/GBSA binding energy; the second-best compound, montelukast, is an approved drug used in the treatment of asthma and allergic rhinitis; the third-best compound, ChEMBL288347, is a bioactive compound. Bromocriptine and saquinavir are other approved drugs that also demonstrate stability in the active site of Mpro, albeit their relative binding energies are low compared to the N3 inhibitor. This study provides useful insights into de novo protein design and novel inhibitor development, which could reduce the cost and time required for the discovery of a potent drug to combat SARS-CoV-2.

Molecular level investigation of curcumin self-assembly induced by trigonelline and nanoparticle formation.

Nanoparticle-facilitated drug delivery forms the core of medicine nowadays with the drug being delivered right at the target, reducing side effects and enhancing therapeutic value. Nanoparticles derived from natural compounds are further a point of focus being biocompatible and safe by and large. In this study, we have performed HF/6-31G calculations coupled with intermolecular interaction calculations and nanoscale molecular dynamics simulations to investigate self-assemblage in curcumin induced by trigonelline. Similar to recently reported self-assemblage in curcumin induced by sugar, trigonelline, a natural antidiabetic derived from fenugreek, can also induce auto-catalyzed self-assemblage in curcumin to form nanoparticles. It has been shown that these nanoparticles may be utilized for the delivery of drugs with severe side effects especially for diabetic patients with triple benefit of being antidiabetic, biocompatible and safe. As an example, carriage of antidiabetic drug pioglitazone and anticancer drug taxol have been depicted utilizing nanoparticles of curcumin and trigonelline. Twenty five taxol molecules could be comfortably carried in a 50 nm nanoparticle with an average overall root mean square deviation of 2.89 Å with reference to initial positions. For the first time, this study shows the possibility of developing antidiabetic nanoparticles with plethora of opportunities for diabetic patients. The study is expected to motivate experimental verification and has a long lasting impact in medicinal chemistry.