The COVID-19 pandemic has resulted in 198 million reported infections and more than 4 million deaths as of July 2021 ( covid19.who.int ). Research to identify effective therapies for COVID-19 includes: (1) designing a vaccine as future protection; (2) de novo drug discovery; and (3) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determine two apo structures of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease at ambient temperature by serial femtosecond X-ray crystallography. We employ detailed molecular simulations of selected known main protease inhibitors with the structures and compare binding modes and energies. The combined structural and molecular modeling studies not only reveal the dynamics of small molecules targeting the main protease but also provide invaluable opportunities for drug repurposing and structure-based drug design strategies against SARS-CoV-2.

Electrospun gelatin nanofibrous matrix encapsulating ciprofloxacin (CIP)/hydroxypropyl-beta-cyclodextrin (HPβCD)-inclusion complex (IC) was produced via electrospinning method. Computational modeling indicated that van der Waals forces are the most significant driving forces for the complexation and hydrophobic moiety (piperazinyl) of CIP, which was included in the cavity of HPβCD. The FTIR and XRD studies indicated the formation of CIP/HPβCD host/guest complexation, FTIR also suggested that hydrophobic moiety of CIP is in the HPβCD cavity in parallel with the computational modeling results. The phase solubility diagram demonstrated that the solubility of CIP was enhanced after complexation with HPβCD. SEM images showed that electrospun gelatin nanofibers encapsulating CIP/HPβCD-IC have bead-free morphology with a diameter of˜90 nm. The gelatin nanofibrous mat loaded with CIP/HPβCD-IC has exhibited fast-dissolving character in water compared to gelatin/CIP nanofibrous mat due to the enhanced wettability of the nanofibrous mat by HPβCD and improvement achieved in the solubility of CIP.

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Nuclear factor-κB (NF κB) transcription factors represent a conserved family of proteins that regulate not only immune cells, but also heart cells, glial cells and neurons, playing a fundamental role in various cellular processes. Due to its dysregulation in certain cancer types as well as in chronic inflammation and autoimmune diseases, it has recently been appreciated as an important therapeutic target. The aim of this study was to investigate the binding pocket of NF κB (p50/p65) heterodimer complex in association with NF κB inhibitor IκBα to identify potent ligands via fragment-based e-pharmacophore screening. The ZINC Clean Fragments (~2 million) and the Schrodinger's medically relevant Glide fragments library (~670) were used to create the e-pharmacophore models at the potential binding site of the target which was validated by site mapping. Glide/HTVS docking was conducted followed by re-docking of the top 20% fragments by Glide/SP and Glide/XP protocols. The top-85000 Glide XP-docked fragments were used to generate the e-pharmacophore hypotheses. The Otava small molecule library (~260000 drug-like molecules) and additional 85 known NF κB inhibitors were screened against the derived e-pharmacophore models. The top-1000 high-scored molecules, which were well aligned to the e-pharmacophore models, from the Otava small molecule library, were then docked into the binding pocket. Finally, the selected 88 hit molecules and the 85 known inhibitors were analyzed by the MetaCore/MetaDrug™ platform, which uses developed binary QSAR models for therapeutic activity prediction as well as pharmacokinetic and toxicity profile predictions of screening molecules. Ligand selection criteria led to the refinement of 3 potent hit molecules using molecular dynamics (MD) simulations to better investigate their structural and dynamical profiles. The selected hit molecules had a low toxicity and a significant therapeutic potential for heart failure, antiviral activity, asthma and depression, all conditions in which NF κB plays a critical role. These hit ligands were also structurally stable at the NF-κB/IκBα complex as per the MD simulations and MM/GBSA analysis. Two of these ligands (Otava IDs: 1426436 and 6248112) were energetically more favorable and therefore are hypothesized to be more potent. Identifying new potent NF κB/IκBα inhibitors may thus present a novel therapy for inflammation-mediated conditions as well as cancer, facilitating more efficient research, and leading the way to future drug development efforts.