Targeting the Fusion Process of SARS-CoV-2 Infection by Small Molecule Inhibitors

SARS-CoV-2 is an enveloped virus that requires membrane fusion for entry into host cells. Since the fusion process is relatively conserved among enveloped viruses, we tested our HCV fusion inhibitors, dichlorcyclizine and fluoxazolevir, against SARS-CoV-2.

Thalidomide-based inhibitor for TNF-α: designing and Insilico evaluation

Background Inflammatory diseases are the vast array of disorders caused by inflammation. During most inflammatory events, many cytokines expressions were modulated, and one such cytokine is tumor necrosis factor-alpha (TNF-α). TNF-α is mainly secreted by monocytes and macrophages. Notably, it has been proposed as a therapeutic target for several diseases. The anti-TNF biology approach is mainly based on monoclonal antibodies. The fusion protein and biosimilars are prevalent in treating inflammation for decades. Only a few small molecule inhibitors are available to inhibit the expression of TNF-α, and one such promising drug was thalidomide. Therefore, the study was carried out to design thalidomide-based small molecule inhibitors for TNF-α. The main objective of our study is to design thalidomide analogs to inhibit TNF-α using the insilico approach. Results Several thalidomide analogs were designed using chemsketch. After filtration of compounds through ‘Lipinski rule of 5’ by Molinspiration tool, as a result, five compounds were selected. All these compounds were subjected to molecular docking, and the study showed that all five compounds had good binding energy. However, based on ADMET predictions, two compounds (S3 and S5) were eliminated. Conclusions Our preliminary results suggest that S1, S2, S4 compounds showed potential ligand binding capacity with TNF-α and, interestingly, with limited or no toxicity. Our preliminary investigation and obtained results have fashioned more interest for further in vitro studies.

In vitro characterization of a small molecule PD-1 inhibitor that targets the PD-l/PD-L1 interaction

Targeting the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) axis with monoclonal antibodies (mAbs) represents a crucial breakthrough in anticancer therapy, but mAbs are limited by their poor oral bioavailability, adverse events in multiple organ systems, and primary, adaptive, and acquired resistance, amongst other issues. More recently, the advent of small molecule inhibitors that target the PD-1/PD-L1 axis have shown promising cellular inhibitory activity and the potential to counteract the disadvantages of mAbs. In this study, structure-based virtual screening identified small molecule inhibitors that effectively inhibited the PD-1/PD-L1 interaction. Six of those small molecule inhibitors were applied to cell-based experiments targeting PD-1: CH-1, CH-2, CH-3, CH-4, CH-5, and CH-6. Of all 6, CH-4 displayed the lowest cytotoxicity and strongest inhibitory activity towards the PD-1/PD-L1 interaction. The experiments revealed that CH-4 inhibited the interaction of soluble form PD-L1 (sPD-L1) with PD-1 surface protein expressed by KG-1 cells. Investigations into CH-4 analogs revealed that CH-4.7 effectively blocked the PD-1/sPD-L1 interaction, but sustained the secretion of interleukin-2 and interferon-γ by Jurkat cells. Our experiments revealed a novel small molecule inhibitor that blocks the interaction of PD-1/sPD-L1 and potentially offers an alternative PD-1 target for immune checkpoint therapy.

Small-molecule degraders of cyclin-dependent kinase protein: a review

Proteolysis-targeting chimeras are a new modality of chemical tools and potential therapeutics involving the induction of protein degradation. Cyclin-dependent kinase (CDK) protein, which is involved in cycles and transcription cycles, participates in regulation of the cell cycle, transcription and splicing. Proteolysis-targeting chimeras targeting CDKs show several advantages over traditional CDK small-molecule inhibitors in potency, selectivity and drug resistance. In addition, the discovery of molecule glues promotes the development of CDK degraders. Herein, the authors describe the existing CDK degraders and focus on the discussion of the structural characteristics and design of these degraders.

New Inhibitors of Laccase and Tyrosinase by Examination of Cross-Inhibition between Copper-Containing Enzymes

Coppers play crucial roles in the maintenance homeostasis in living species. Approximately 20 enzyme families of eukaryotes and prokaryotes are known to utilize copper atoms for catalytic activities. However, small-molecule inhibitors directly targeting catalytic centers are rare, except for those that act against tyrosinase and dopamine-β-hydroxylase (DBH). This study tested whether known tyrosinase inhibitors can inhibit the copper-containing enzymes, ceruloplasmin, DBH, and laccase. While most small molecules minimally reduced the activities of ceruloplasmin and DBH, aside from known inhibitors, 5 of 28 tested molecules significantly inhibited the function of laccase, with the Ki values in the range of 15 to 48 µM. Enzyme inhibitory kinetics classified the molecules as competitive inhibitors, whereas differential scanning fluorimetry and fluorescence quenching supported direct bindings. To the best of our knowledge, this is the first report on organic small-molecule inhibitors for laccase. Comparison of tyrosinase and DBH inhibitors using cheminformatics predicted that the presence of thione moiety would suffice to inhibit tyrosinase. Enzyme assays confirmed this prediction, leading to the discovery of two new dual tyrosinase and DBH inhibitors.

Peptide Inhibitors of Kv1.5: An Option for the Treatment of Atrial Fibrillation

The human voltage gated potassium channel Kv1.5 that conducts the IKur current is a key determinant of the atrial action potential. Its mutations have been linked to hereditary forms of atrial fibrillation (AF), and the channel is an attractive target for the management of AF. The development of IKur blockers to treat AF resulted in small molecule Kv1.5 inhibitors. The selectivity of the blocker for the target channel plays an important role in the potential therapeutic application of the drug candidate: the higher the selectivity, the lower the risk of side effects. In this respect, small molecule inhibitors of Kv1.5 are compromised due to their limited selectivity. A wide range of peptide toxins from venomous animals are targeting ion channels, including mammalian channels. These peptides usually have a much larger interacting surface with the ion channel compared to small molecule inhibitors and thus, generally confer higher selectivity to the peptide blockers. We found two peptides in the literature, which inhibited IKur: Ts6 and Osu1. Their affinity and selectivity for Kv1.5 can be improved by rational drug design in which their amino acid sequences could be modified in a targeted way guided by in silico docking experiments.