Suman Shaw

Cancer remains one of the leading causes of death worldwide, with current therapies often limited by side effects, recurrence of metastatic cancer, and poor patient compliance. The urgent need for new anticancer agents with novel mechanisms of action has made phosphoinositide 3‐kinase (PI3K) a promising target due to its role in cell growth, proliferation, and survival. In this study, we employed a comprehensive computational approach, beginning with the generation of a 3D pharmacophore model of PI3K using atomic property field (APF) alignment of two crystal structures (PDB IDs: 4L23 and 8TSC). Virtual screening of 2,500 MolScreen ligands and 2,431,025 ChEMBL ligands was performed, identifying 350 ligands with promising interactions with PI3K. ADMET analysis and docking scores were calculated for these, and 200 ligands showed favorable pharmacokinetic or drug‐like properties. Among them, CHEMBL2163908 emerged as the top candidate, exhibiting the highest docking score and promising drug‐likeness properties. Further molecular dynamics (MD) simulations of CHEMBL2163908 for 200 ns confirmed its stable binding at the PI3K active site. These findings highlight CHEMBL2163908 as a potential lead for the development of novel PI3K inhibitors in anticancer therapy.

Backgrounds: This study explores the design of substituted tetrahydroquinoline (THQ) derivatives and their synthesis as possible inhibitors of mTOR inhibitors for targeted cancer therapy. Methods: Inspired by the structural characteristics of known mTOR inhibitors, eight novel derivatives were synthesized, characterized using mass spectroscopy, ¹H, and ¹³C NMR, and evaluated for anticancer activity. Results: Computational studies, including molecular docking and molecular dynamics (MD) simulations, highlighted the derivative’s strong binding interaction and stability within the mTOR active site. Assays for in vitro cytotoxicity showed strong and specific anticancer action against cell lines of triple-negative breast cancer, lung cancer, and breast cancer while causing negligible impact on healthy cells. Conclusions: Compound 10e emerged as the most promising candidate, displaying exceptional activity against A549 cells (IC₅₀ = 0.033 µM) and inducing apoptosis in a dose-dependent manner, surpassing standard agents, like Everolimus and 5-flurouracil. Structure–activity relationship analysis revealed that incorporating trifluoromethyl and morpholine moieties significantly enhanced selectivity and potency. MD simulations further validated these findings, confirming stable protein-ligand interactions and favorable dynamics over a 100-ns simulation period. Collectively, this study underscores the therapeutic potential of THQ derivatives, particularly compound 10e, as promising mTOR inhibitors with potential applications in lung cancer treatment.

This study explores the design and synthesis of substituted tetrahydroquinoline (THQ) derivatives as potential mTOR inhibitors for targeted cancer therapy. Inspired by the structural characteristics of known mTOR inhibitors, eight novel derivatives were synthesized, characterized using advanced spectroscopic techniques, and evaluated for anticancer activity. Computational studies, including molecular docking and molecular dynamics (MD) simulations, highlighted the derivative's strong binding affinity and stability within the mTOR active site. In-vitro cytotoxicity assays demonstrated potent and selective anticancer activity against A549, MCF-7, and MDA-MB-231 cancer cell lines, with minimal toxicity toward normal cells. Compound 10e emerged as the most promising candidate, displaying exceptional activity against A549 cells (IC₅₀ = 0.033 µM) and inducing apoptosis in a dose-dependent manner, surpassing standard agents like Everolimus and 5 Flurouracil. Structure-activity relationship analysis revealed that incorporating trifluoromethyl and morpholine moieties significantly enhanced selectivity and potency. MD simulations further validated these findings, confirming stable protein-ligand interactions and favorable dynamics over a 100-ns simulation period. Collectively, this study underscores the therapeutic potential of THQ derivatives, particularly compound 10e, as promising mTOR inhibitors with potential applications in lung cancer treatment.

There is a need to develop innovative, safe, and more effective treatment methods for lung cancer due to obstacles including resistance, side effects, and low bioavailability, among others related to present medicines. Our previous research findings gave some promising results of tetrahydroquinoline (THQ) derivatives as mTOR inhibitors for the treatment of lung cancer. The current research has employed certain integrated computational techniques to enhance the effectiveness of THQ derivatives. Various computational methods, like the generation of the pharmacophore model, virtual screening, and QSAR modeling were employed to achieve the goal, and their results were connected to develop novel THQ analogues. This study revealed that among 48 newly designed THQ derivatives, the compound UC_1 indicated the XP Gscore of −9.378 kcal/mol and also showed the key amino acid interactions with the mTOR protein viz. Gln2167, Val2240. Interestingly, compound UC_1 showed a better binding affinity with the mTOR protein compared to the clinical trial molecules viz. AZD‐8055 and AZD‐2014. The molecular dynamics simulations (100 ns) along with each output give a shred of strong evidence that the designed THQ derivative (UC_1) has all the required features in terms of inhibiting mTOR protein for the treatment of lung cancer.

Efforts have been made to find an efficient scaffold (and its substitution) that can be used for the treatment of lung cancer via mTOR inhibition. A detailed literature search was carried out for p... Graphical abstract