Identification of NSP3 (SH2D3C) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from Allium sativum L. as Therapeutic Candidates

Abstract

The multi-domain non-structural protein 3 (NSP3) is an oncogenic molecule that has been concomitantly implicated in the progression of coronavirus infection. However, its oncological role in lung cancer and whether it plays a role in modulating the tumor immune microenvironment is not properly understood. In the present in silico study, we demonstrated that NSP3 (SH2D3C) is associated with advanced stage and poor prognoses of lung cancer cohorts. Genetic alterations of NSP3 (SH2D3C) co-occurred inversely with Epidermal Growth Factor Receptor (EGFR) alterations and elicited its pathological role via modulation of various components of the immune and inflammatory pathways in lung cancer. Our correlation analysis suggested that NSP3 (SH2D3C) promotes tumor immune evasion via dysfunctional T-cell phenotypes and T-cell exclusion mechanisms in lung cancer patients. NSP3 (SH2D3C) demonstrated a high predictive value and association with therapy resistance in lung cancer, hence serving as an attractive target for therapy exploration. We evaluated the in silico drug-likeness and NSP3 (SH2D3C) target efficacy of six organosulfur small molecules from Allium sativum using a molecular docking study. We found that the six organosulfur compounds demonstrated selective cytotoxic potential against cancer cell lines and good predictions for ADMET properties, drug-likeness, and safety profile. E-ajoene, alliin, diallyl sulfide, 2-vinyl-4H-1,3-dithiin, allicin, and S-allyl-cysteine docked well into the NSP3 (SH2D3C)-binding cavity with binding affinities ranging from –4.3~–6.70 Ă and random forest (RF) scores ranging from 4.31~5.26 pKd. However, S-allyl-cysteine interaction with NSP3 (SH2D3C) is unfavorable and hence less susceptible to NSP3 ligandability. In conclusion, our study revealed that NSP3 is an important onco-immunological biomarker encompassing the tumor microenvironment, disease staging and prognosis in lung cancer and could serve as an attractive target for cancer therapy. The organosulfur compounds from A. sativum have molecular properties to efficiently interact with the binding site of NSP3 and are currently under vigorous preclinical study in our laboratory.

Identification of a novel immune-inflammatory signature of COVID-19 infections, and evaluation of pharmacokinetics and therapeutic potential of RXn-02, a novel small-molecule derivative of quinolone

“…Molecular docking is a widely explored simulation tool for modeling the potential binding efficacy of a small-molecule drug candidate and its targeted protein molecules, and for evaluating interactions between the protein-ligand docked complex [ 89 , [100] , [101] , [102] ], thus providing insights into the biological activities of the drug candidate and aiding drug discovery and development [ [103] , [104] , [105] , [106] , [107] ].…”

Luteolin-Rich Extract of Thespesia garckeana F. Hoffm. (Snot Apple) Contains Potential Drug-Like Candidates and Modulates Glycemic and Oxidoinflammatory Aberrations in Experimental Animals

“…Luteolin's Properties for Targeting Glucose-Metabolizing Enzymes and an Inflammatory Mediator. Molecular docking is an innovative and widely approved strategies for mimicking a small-molecule interaction with a target receptor/protein [57,100,101]. It provides qualitative and quantitative estimation of the affinity between a compound and the corresponding protein/receptor [102].…”

In silico study of novel niclosamide derivatives, SARS-CoV-2 nonstructural proteins catalytic residue-targeting small molecules drug candidates

“…Scaffold-hopping of bioactive compounds containing different core structures is an important approach in medicinal chemistry for the design and development of new drugs ( Lawal et al, 2017 ). Medicinal plants have been used for the effective treatment of microbial infections and several kinds of human diseases ( Lawal et al, 2015 , Iwu, 1993 , Wu et al, 2022 , Onikanni et al, 2021 , Yeh et al, 2021 , Wu et al, 2021 , Salleh et al, 2021 ), and are considered to produce least or no adverse effects in clinical trials when compared to conventional drugs ( Spiller and Sawyer, 2006 , Samples, 2004 ). Biphenyl, flavones, and isoflavones are important natural product backbones, and several bioactive compounds containing these backbones were reported to have a vast range of biological activities, including antioxidative, anti-atherosclerosis, muscle relaxant, antimicrobial, anti-inflammatory, anticancer, and antiviral effects ( Erlund, 2004 , Saakre et al, 2021 ).…”