Discovery of potent Covid-19 main protease inhibitors using integrated drug-repurposing strategy.

The emergence and rapid spreading of novel SARS-CoV-2 across the globe represent an imminent threat to public health. Novel antiviral therapies are urgently needed to overcome this pandemic. Given the significant role of the main protease of Covid-19 for virus replication, we performed a drug-repurposing study using the recently deposited main protease structure, 6LU7. For instance, pharmacophore- and e-pharmacophore-based hypotheses such as AARRH and AARR, respectively, were developed using available small molecule inhibitors and utilized in the screening of the DrugBank repository. Further, a hierarchical docking protocol was implemented with the support of the Glide algorithm. The resultant compounds were then examined for their binding free energy against the main protease of Covid-19 by means of the Prime-MM/GBSA algorithm. Most importantly, the machine learning-based AutoQSAR algorithm was used to predict the antiviral activities of resultant compounds. The hit molecules were also examined for their drug-likeness and toxicity parameters through the QikProp algorithm. Finally, the hit compounds activity against the main protease was validated using molecular dynamics simulation studies. Overall, the present analysis yielded two potential inhibitors (DB02986 and DB08573) that are predicted to bind with the main protease of Covid-19 better than currently used drug molecules such as N3 (cocrystallized native ligand), lopinavir, and ritonavir.

Discovery of Potent Neuraminidase Inhibitors Using a Combination of Pharmacophore-Based Virtual Screening and Molecular Simulation Approach.

Neuraminidase (NA), a surface protein, facilitates the release of nascent virus and thus spreads infection. It has been renowned as a potential drug target for influenza A virus infection. The drugs such as oseltamivir, zanamivir, peramivir, and laninamivir are approved for the treatment of influenza infection. Additionally, investigational drugs namely MK2206, tamiphosphor, crenatoside, and dehydroepiandrosterone (DHEA) are also available for the treatment. However, recent outbreaks of highly pathogenic and drug-resistant influenza A strains highlighted the need to discover novel NA inhibitor. Keeping this in mind, in the current investigation, an effort was made to ascertain potent inhibitors using pharmacophore-based virtual screening and docking approach. A 3D pharmacophore model was generated based on the chemical features of approved and investigational NA inhibitors using PHASE module of Schrödinger suite. The model consists of two hydrogen bond acceptors (A), one hydrogen bond donor (D), and one positively charged group (P), AADP. Subsequently, molecules with same pharmacophoric features were screened from among the two million compounds available in the ZINC database using the generated pharmacophore hypothesis. Ligand filtration was also done to obtain an efficient collection of hit molecules by employing Lipinski "rule of five" using Qikprop module. Finally, the screened molecule was subjected to docking and molecular dynamic simulations to examine the inhibiting activity of the compounds. The results of our analysis suggest that "acebutolol hydrochloride" (156792) could be the promising candidates for the treatment of influenza A virus infection.

Host-guest interactions in the confined geometries formed from molecular aggregates of push-pull molecules.

We have considered push-pull molecules, aminonitroacetylene and aminonitrodiacetylene (O2N-(C≡C)n-NH2; n = 1 and 2) as the basic units to design a series of molecular aggregates containing favorable hydrogen bonding interactions. Linear, closed, and stacked geometries of dimers, trimers, tetramers, and pentamers formed from these molecules are found to have very good stabilization energies due to the strong hydrogen bonding abilities of the terminal -NO2 and -NH2 groups. The closed hydrogen-bonded assemblies can act as supramolecular hosts for accommodating some molecules and ions as guests. We have been able to find substantial host-guest interaction energies for the complexes of the hydrogen-bonded closed assemblies with some highly reactive molecules like hexahydro-1,3,5-trinitro-s-triazine (RDX), octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), pentafluoroethane (R-125), and difluoromethane (R-32). Further investigations on the interaction of the ions Li(+), Na(+), K(+), Mg(2+), Ca(2+), Al(3+), F(-), Cl(-), and Br(-) with the monomers as well as the oligomers reveal the formation of strong ion-σ complexes, unlike the conventional weak ion-π complexes found in similar acetylenic systems without the end groups. This opens up the possibility of tuning the nature of ionic interactions in π-systems by varying the terminal groups.