Tetraasteranes as homologues of cubanes: effective scaffolds for drug discovery.

Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market for a variety of applications, but one notable omission is that of tetraasteranes, which are homologues of cubanes belonging to a class of polycyclic hydrocarbon cage compounds. Tetraasteranes exhibit potential as scaffolds in drug discovery due to their identical cyclobutane structures and rigid conformation resembling cubanes. Based on the studies of the physical and chemical properties of tetraasteranes by density functional theory, three series of compounds were designed as homologues of cubanes by the substitution of cubane scaffolds in pharmaceuticals with tetraasteranes. Their potential for pharmaceutical applications was evaluated in silico by molecular docking and dynamics simulations. Their pharmacokinetic and physicochemical properties were studied by the ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis. The results indicate that tetraasteranes may be scaffolds as novel bioisosteres of cubanes, as well as hydrogen bond donors or acceptors, which enhance the affinity between ligands and receptors with more stable binding behavior and feasible tolerability in ADMET. All these findings provide new opportunities for tetraasteranes to serve as effective pharmaceutical scaffolds for drug discovery and to accelerate the drug discovery process by repurposing both new and old commercial compounds.

Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors.

Influenza A virus is the main cause of worldwide epidemics and annual influenza outbreaks in humans. In this study, a virtual screen was performed to identify compounds that interact with the PB2 cap-binding domain (CBD) of influenza A polymerase. A virtual screening workflow based on Glide docking was used to screen an internal database containing 8417 molecules, and then the output compounds were selected based on solubility, absorbance, and structural fingerprints. Of the 16 compounds selected for biological evaluation, six compounds were identified that rescued cells from H1N1 virus-mediated death at non-cytotoxic concentrations, with EC50 values ranging from 2.5-55.43 µM, and that could bind to the PB2 CBD of H1N1, with Kd values ranging from 0.081-1.53 µM. Molecular dynamics (MD) simulations of the docking complexes of our active compounds revealed that each compound had its own binding characteristics that differed from those of VX-787. Our active compounds have novel structures and unique binding modes with PB2 proteins, and are suitable to serve as lead compounds for the development of PB2 inhibitors. An analysis of the MD simulation also helped us to identify the dominant amino acid residues that play a key role in binding the ligand to PB2, suggesting that we should focus on increasing and enhancing the interaction between inhibitors and these major amino acids during lead compound optimization to obtain more active PB2 inhibitors.

Design, Synthesis, Evaluation and Molecular Dynamics Simulation of Dengue Virus NS5-RdRp Inhibitors.

Dengue virus (DENV) is a major mosquito-borne human pathogen in tropical countries; however, there are currently no targeted antiviral treatments for DENV infection. Compounds 27 and 29 have been reported to be allosteric inhibitors of DENV RdRp with potent inhibitory effects. In this study, the structures of compounds 27 and 29 were optimized using computer-aided drug design (CADD) approaches. Nine novel compounds were synthesized based on rational considerations, including molecular docking scores, free energy of binding to receptor proteins, predicted Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) parameters, structural diversity, and feasibility of synthesis. Subsequently, the anti-DENV activity was assessed. In the cytopathic effect (CPE) assay conducted on BHK-21 cells using the DENV2 NGC strain, both SW-b and SW-d demonstrated comparable or superior activity against DENV2, with IC50 values of 3.58 ± 0.29 µM and 23.94 ± 1.00 µM, respectively, compared to that of compound 27 (IC50 = 19.67 ± 1.12 µM). Importantly, both SW-b and SW-d exhibited low cytotoxicity, with CC50 values of 24.65 µmol and 133.70 µmol, respectively, resulting in selectivity indices of 6.89 and 5.58, respectively. Furthermore, when compared to the positive control compound 3'-dATP (IC50 = 30.09 ± 8.26 µM), SW-b and SW-d displayed superior inhibitory activity in an enzyme inhibitory assay, with IC50 values of 11.54 ± 1.30 µM and 13.54 ± 0.32 µM, respectively. Molecular dynamics (MD) simulations elucidated the mode of action of SW-b and SW-d, highlighting their ability to enhance π-π packing interactions between benzene rings and residue W795 in the S1 fragment, compared to compounds 27 and 29. Although the transacylsulphonamide fragment reduced the interaction between T794 and NH, it augmented the interaction between R729 and T794. In summary, our study underscores the potential of SW-b and SW-d as allosteric inhibitors targeting the DENV NS5 RdRp domain. However, further in vivo studies are warranted to assess their pharmacology and toxicity profiles.