Poor bioavailability due to the inability to cross the cell membrane is one of the major reasons for the failure of a drug in clinical trials. We have used molecular dynamics simulations to predict the membrane permeability of natural drugs—withanolides (withaferin-A and withanone) that have similar structures but remarkably differ in their cytotoxicity. We found that whereas withaferin-A, could proficiently transverse through the model membrane, withanone showed weak permeability. The free energy profiles for the interaction of withanolides with the model bilayer membrane revealed that whereas the polar head group of the membrane caused high resistance for the passage of withanone, the interior of the membrane behaves similarly for both withanolides. The solvation analysis further revealed that the high solvation of terminal O5 oxygen of withaferin-A was the major driving force for its high permeability; it interacted with the phosphate group of the membrane that led to its smooth passage across the bilayer. The computational predictions were tested by raising and recruiting unique antibodies that react to withaferin-A and withanone. The time-lapsed analyses of control and treated cells demonstrated higher permeation of withaferin-A as compared to withanone. The concurrence between the computation and experimental results thus re-emphasised the use of computational methods for predicting permeability and hence bioavailability of natural drug compounds in the drug development process.

SARS-CoV-2 is liable for the worldwide coronavirus disease (COVID-19) exigency. This pandemic created the need for all viable treatment strategies available in the market. In this scenario, computeraided drug design techniques can be efficiently applied for the quick identification of promising drug repurposing candidates. In the current study, we applied the molecular docking approach in conjugation with molecular dynamics (MD) simulations to find out potential inhibitors against M pro of SARS-CoV-2 from previously reported SARS-3CL protease inhibitors. Our results showed that N-substituted isatin derivatives and pyrazolone compounds could be used as a potent inhibitor and may possess an anti-viral activity against SARS-CoV-2. However, further experimental investigation and validation of the selected hits are required to find out their suitability for clinical trials.

The photophysics of green fluorescent protein (GFP) is remarkable because of its exceptional property of excited state proton transfer (ESPT) and the presence of a functional proton wire. Another interesting property of wild‐type GFP is that its absorption and fluorescence excitation spectra are sensitive to the presence of polar organic solvents even at very low concentrations. Here, we use a combination of methodologies including site‐specific mutagenesis, absorption spectroscopy, steady‐state and time‐resolved fluorescence measurements and all‐atom molecular dynamics simulations in explicit solvent, to uncover the mechanism behind the unique spectral sensitivity of GFP toward organic solvents. Based on the evidences provided herein, we suggest that organic solvent‐induced changes in the proton wire prevent ground state movement of a proton through the wire and thus bring about the spectral changes observed. The present study can not only help to understand the mechanism of proton transfer by further dissecting the intricate steps in GFP photophysics but also encourages to develop GFP‐based organic solvent biosensors.

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N-heterocyclic carbene complexes comprise mesoionic carbenes (MICs) have emerged as a huge asset in the field of organometallic chemistry and particularly their applications in homogeneous catalysis. However, such complexes containing mixed chiral-MIC and phosphine donor ligands are rare and relatively less explored. In this manuscript, three new palladium(II) complexes with mixed MIC/Py/PPh 3 /PCy 3 donor set ligands possessing chirality at MIC center are presented. Nuclear magnetic resonance (NMR) spectroscopy and electrospray ionisation (ESI) mass spectrometry analysis have been used to characterize these complexes. Single crystal X-ray diffraction (XRD) was also used to establish the structure of Pd II complex possessing mixed MIC/PPh 3 ligands. The new palladium(II) complexes with a combination of MIC and PR 3 (R = Ph and Cy) ligands have been found as effective precatalysts and provided excellent yields in Suzuki-Miyaura coupling, Sonogashira coupling, and copper-free α-arylation reactions. It is observed that the Pd II complexes with MIC/PR 3 donor set of ligands show superior activity compared with the complexes with mixed MIC/Py set of ligands in α-arylation of amide and Sonogashira coupling reactions. The catalytic outcomes have also been supported with preliminary electrochemical measurements.