Biology subjects

Fadel, S.

Publications and source records attributed to Fadel, S..

3 recordsLinked to original sources

bioRxiv2024

Generative AI for Drug Discovery: A GPT-2 and LSTM Based Models for Designing EGFR Inhibitors

The design of novel EGFR inhibitors is a critical focus in cancer drug discovery. This study leverages generative AI models, specifically fine-tuned GPT-2 and LSTM architectures, to generate new chemical structures targeting the Epidermal Growth Factor Receptor (EGFR). The models were trained on a curated dataset of approximately 500,000 bioactive ligands from the ChEMBL database, with SMILES strings as input. After generating a batch of 1,000 molecules, post-generation filtering was applied based on Lipinskis rule of five, Quantitative Estimate of Drug-likeness (QED), and Synthetic Accessibility Scores (SAS) to ensure drug-like properties. Molecular docking studies were performed using PyRx with AutoDock Vina, focusing on the crystal structure of EGFR (PDB ID: 1M17). The LSTM model outperformed GPT-2, achieving a higher validity rate (90.98% vs. 52.27%) and similar uniqueness rates, while also producing molecules with stronger binding affinities, ranging from -9.4 to -10.4 kcal/mol. The results indicate that the LSTM model is more effective for generating chemically valid EGFR inhibitors, offering promising candidates for further experimental validation. This study demonstrates the potential of generative AI to accelerate the identification of effective cancer therapeutics.

bioinformatics↗

bioRxiv2024

Inhibition of Acyl-CoA Synthetase Long Chain Isozymes Decreases Multiple Myeloma Cell Proliferation and Causes Mitochondrial Dysfunction

Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5-year survival rate of 59%. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression; however, the underlying mechanisms remain unclear. Acyl-CoA synthetase long-chain family members (ACSLs) convert free long-chain fatty acids into fatty acyl-CoA esters and play key roles in catabolic and anabolic fatty acid metabolism. The Cancer Dependency Map data suggested that ACSL3 and ACSL4 were among the top 25% Hallmark Fatty Acid Metabolism genes that support MM fitness. Here, we show that inhibition of ACSLs in human myeloma cell lines using the pharmacological inhibitor Triascin C (TriC) causes apoptosis and decreases proliferation in a dose- and time-dependent manner. RNA-seq of MM.1S cells treated with TriC for 24 h showed a significant enrichment in apoptosis, ferroptosis, and ER stress. Proteomics of MM.1S cells treated with TriC for 48 h revealed that mitochondrial dysfunction and oxidative phosphorylation were significantly enriched pathways of interest, consistent with our observations of decreased mitochondrial membrane potential and increased mitochondrial superoxide levels. Interestingly, MM.1S cells treated with TriC for 24 h also showed decreased mitochondrial ATP production rates and overall lower cellular respiration. ImplicationsOverall, our data support the hypothesis that suppression of ACSL in human MM cells inhibit their growth and viability, indicating that ACSL proteins may be promising therapeutic targets in treating myeloma progression.

cancer biology↗

bioRxiv2022

More than a ligand: PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I interferon pathway.

Targeting the PD-1/PD-L1 axis has transformed the field of immune-oncology. While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced infection with oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 suppressed type I interferon by promoting a metabolic shift characterized by enhanced glucose uptake and glycolysis rate. Lactate generated from glycolysis was the key metabolite responsible for inhibiting type I interferon responses and enhancing oncolytic virus infection in PD-L1-expressing cells. In addition to adding mechanistic insight into PD-L1 intrinsic function and showing that PD-L1 has a broader impact on immunity and cancer biology besides acting as a ligand for PD-1, our results will also help guide the numerous efforts currently ongoing to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials. Once sentence summaryPD-L1 promotes oncolytic virus efficacy.

cancer biology↗