Synthesis and in silico assessment of thiadiazole scaffolds for anticancer applications: network pharmacology and molecular simulations

The creation of new anticancer drugs is still a top research priority because many cancers still don’t respond well to the treatments that are now available. Monoterpenoids like (R)-carvone are useful building blocks for making novel bioactive compounds. This study synthesized a variety of thiadiazole-based (R)-carvone derivatives and assessed their efficacy in inhibiting AKT1, a pivotal oncogenic kinase implicated in cancer cell proliferation and survival. We used HRMS, 1 H/ 13 C-NMR, and IR spectroscopy to figure out the structures of the compounds we made. We used Doxorubicin as a reference medication to test the in vitro cytotoxic activity of the compounds against human cancer cell lines PC3 (prostate), A549 (lung), and MCF-7 (breast). To corroborate the experimental results, extensive in silico investigations were conducted, encompassing density functional theory (DFT) calculations, molecular docking, ADMET profiling, network pharmacology analysis, and 100 ns molecular dynamics (MD) simulations. Among the produced derivatives ( 4a & 4b ), compound 4b demonstrated the highest cytotoxic activity against PC3 cells, exhibiting an IC 50 value of 16.12 ± 1.25 µM. Molecular docking experiments showed that compounds 4a and 4b have a greater affinity for AKT1 than the conventional inhibitor Capivasertib. MD simulations validated the establishment of a stable AKT1–4b complex, with RMSD values ranging from 2.4 to 2.8 Å. MM/GBSA free-energy computations, in conjunction with PCA, PDF, and FEL analyses, further corroborated the stability and advantageous binding characteristics of compound 4b . The results show that compound 4b is a good framework for developing more anticancer drugs that target AKT1.