The ongoing pandemic of COVID-19 caused by the novel coronavirus Syndrome-Coronavirus-2 (SARS-CoV-2) is an emerging, rapidly evolving situation. 1 Coronaviruses (CoV) are enveloped viruses with a positive single-stranded RNA virus, which are widely distributed in humans and animals and cause respiratory infections in humans. 2 Study reported that SARS-CoV-2 enters the cells through its predicated receptor angiotensin converting enzyme 2 (ACE2). 3 Unfortunately, until now, there are no specific/targeted drugs or vaccines, and in many parts of the world, the number of SARS-CoV-2-positive patients are increasing. As of 20 April 2020, in total, 2 486 597 cases and 170 582 deaths have been confirmed around the world, suggesting that the overall death rate of COVID-19 was 6.86%. D-dimer is a specific degradation product produced by fibrin monomer cross-linking with activated factor XIII and then hydrolysed by plasmin, and is a specific marker of fibrinolysis process. 4 Excluded typical manifestation of pneumonia and acute respiratory symptoms, COVID-19 patients also have abnormal D-dimer concentration in the serum, but the results are controversial. A recent

G-protein-coupled receptor (GPCR) is an important target class of proteins for drug discovery, with over 27% of FDA-approved drugs targeting GPCRs. However, being a membrane protein, it is difficult to obtain the 3D crystal structures of GPCRs for virtual screening of ligands by molecular docking. Thus, we evaluated the virtual screening performance of homology models of human GPCRs with respect to the corresponding crystal structures. Among the 19 GPCRs involved in this study, we observed that 10 GPCRs have homology models that have better or comparable performance with respect to the corresponding X-ray structures, making homology models a viable choice for virtual screening. For a small subset of GPCRs, we also explored how certain methods like consensus enrichment and sidechain perturbation affect the utility of homology models in virtual screening, as well as the selectivity between agonists and antagonists. Most notably, consensus enrichment across multiple homology models often yields results comparable to the best performing model, suggesting that ligand candidates predicted with consensus scores from multiple models can be the optimal option in practical applications where the performance of each model cannot be estimated.

G-protein-coupled receptor (GPCR) is an important target class of proteins for drug discovery, with over 27% of FDA-approved drugs targeting GPCRs. However, being a membrane protein, it is difficult to obtain the 3D crystal structures of GPCRs for virtual screening of ligands by molecular docking. Thus, we evaluated the virtual screening performance of homology models of human GPCRs with respect to the corresponding crystal structures. Among the 19 GPCRs involved in this study, we observed that 10GPCRs have homology models that have better or comparable performance with respect to the corresponding X-ray structures, making homology models a viable choice for virtual screening. For a small subset of GPCRs, we also explored how certain methods like consensus enrichment and sidechain perturbation affect the utility of homology models in virtual screening, as well as the selectivity between agonists and antagonists. Most notably, consensus enrichment across multiple homology models often yields results comparable to the best performing model, suggesting that ligand candidates predicted with consensus scores from multiple models can be the optimal option in practical applications where the performance of each model cannot be estimated.

Background. As a new kind of noncoding RNAs, circular RNAs (circRNAs) have been substantiated to be involved in multiple biological processes. Accumulating studies indicate that circular RNAs (circRNAs) regulate the development of cancers by acting as miRNA sponges. However, the role of circRNAs in endometrial cancer (EC) is rarely reported. This study was aimed at investigating the functional roles of circSLC6A6 in EC. Methods. The qRT-PCR assay was performed to detect the circSLC6A6 expression in EC tissues and cell lines. The luciferase reporter assay was performed to explore the connection between circSLC6A6 and miR-497-5p as well as the connection between miR-497-5p and PI4KB. The colony formation assay, EdU assay, wound healing assay, and transwell assay were performed to examine the proliferation, migration, and invasion of EC cells. The in vivo assay was performed to reveal the function of circSLC6A6 in tumorigenesis. Results. We found that circSLC6A6 was highly expressed in both EC tissues and cells. And circSLC6A6 promoted the proliferation, migration, and invasion of EC cells in vitro. In vivo, circSLC6A6 promoted tumor growth. Besides, a mechanistic study demonstrated that circSLC6A6 could regulate tumor-associated signaling PI4KB/hedgehog pathway by sponging miR-497-5p. Conclusion. This study illustrates that circSLC6A6 plays a role in promoting EC progression via the miR-497-5p-mediated PI4KB/hedgehog pathway. Our study may provide a potential novel biomarker for EC diagnosis or treatment.

Summary Here we report a molecular docking-based approach to identify small molecules that can target the β-catenin (β-cat)-TCF4 protein-protein interaction (PPI), a key effector complex for nuclear Wnt signaling activity. Specifically, we developed and optimized a computational model of β-cat using publicly available β-cat protein crystal structures, and existing β-cat-TCF4 interaction inhibitors as the training set. Using our computational model to an in silico screen predicted 27 compounds as good binders to β-cat, of which 3 were identified to be effective against a Wnt-responsive luciferase reporter. In vitro functional validation experiments revealed GB1874 as an inhibitor of the Wnt pathway that targets the β-cat-TCF4 PPI. GB1874 also affected the proliferation and stemness of Wnt-addicted colorectal cancer (CRC) cells in vitro . Encouragingly, GB1874 inhibited the growth of CRC tumor xenografts in vivo , thus demonstrating its potential for further development into therapeutics against Wnt-associated cancer indications.

Background: Recent studies have found that programmed death ligand 1 (PD-L1) might be involved in chemotherapy resistance in non-small cell lung cancer (NSCLC). Arsenic sulfide (As 4 S 4 ) has been recognized to have antitumor activities and enhance the cytotoxic effect of chemotherapy drugs. In this study, we aimed to verify the relationship between PD-L1 and cisplatin (DDP) resistance and identify whether As 4 S 4 could reverse DDP resistance through targeting PD-L1 in NSCLC. Methods: The effect of As 4 S 4 and DDP on cell proliferation and apoptosis was investigated in NSCLC cell lines. The expression of p53 and PD-L1 proteins was measured by western blotting analysis. The levels of miR-34a-5p, miR-34a-3p and PD-L1 in cells were measured by real-time qPCR analysis. Mouse xenograft models were established by inoculation with A549/DDP (DDP-resistant) cells. Results: Depletion of PD-L1 inhibited DDP resistance in A549/DDP and H1299/DDP cells. As 4 S 4 was capable of sensitizing A549/DDP cells to DDP by enhancing apoptosis. As 4 S 4 upregulated p53 expression and downregulated PD-L1 expression in A549/DDP cells. As 4 S 4 increased miR-34a-5p level in A549/DDP cells. Inhibition of p53 by PFT-α partially restored the levels of PD-L1 and miR-34a-5p. Pretreatment with PFT-α suppressed the apoptosis rate induced by cotreatment of As 4 S 4 and DDP in A549/DDP cells. Cotreatment of DDP and As 4 S 4 notably reduced the tumor size when compared with DDP treatment alone in vivo. Conclusions: Upregulation of PD-L1 was correlated with DDP resistance in NSCLC cells. Mechanistic analyses indicated that As 4 S 4 might sensitize NSCLC cells to DDP through targeting p53/miR-34a-5p/PD-L1 axis.

No abstract

Canonical Wnt signaling is one of the crucial pathways involved in embryonic development and tissue homeostasis. However this pathway is often dysregulated in cancers and thus developing effective inhibitors of Wnt signaling is of great interest in the field. Our strategy for inhibition of Wnt signaling involves disruption of the β-catenin (β-cat)-Tcf4 protein-protein interaction (PPI) complex, which is the key effector for nuclear Wnt signaling activity. Towards this goal, we developed a computational model of β-cat for predicting small molecule binders. Application of our computational model to an in silico screen against a library of more than 10,000 compounds predicted 27 compounds as good binders to β-cat. Through in vitro validation experiments such as Wnt reporter assays, co-immunoprecipitation, and surface plasmon resonance (SPR) studies, we identified compound GB1874 as our most promising candidate for inhibiting the β-cat-Tcf4 PPI. Compound GB1874 also affected the proliferation of Wnt-addicted colorectal cancer (CRC) cells in vitro and in tumor xenograft models in vivo. Notably the in vivo efficacy was associated with minimal systemic toxicity. In summary, we report the identification of a novel disruptor of β-cat-Tcf4 interaction, GB1874, which can serve as a promising small molecule candidate for a Wnt signaling inhibitor. Moreover, our study demonstrates the feasibility of using computational modeling to identify new inhibitors of PPI. Citation Format: Joo-Leng Low, Weina Du, Tenzin Gocha, Oguz Gokce, Xiaoqian Zhang, Daniel G. Yim, Adaikalavan Ramasamy, Hao Fan, Ramanuj DasGupta. Discovery of novel small molecule inhibitors of Wnt signaling through in silico molecular docking [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 509.