In silico exploring the mechanisms of action of diterpenoids from Rabdosia serra against lung cancer through inhibition of the anti-apoptotic pathway

Abstract

Introduction: Apoptosis resistance in non-small cell lung cancer is frequently sustained by pro-survival Bcl-2 family proteins such as Mcl-1, motivating the search for new Mcl-1 inhibitors from natural products, including diterpenoids from Rabdosia serra.

Materials and Methods: An integrated in silico approach was applied to evaluate R. serra diterpenoids as putative Mcl-1 (PDB: 6QFQ) inhibitors, integrating molecular docking, molecular dynamics simulation, MM/GBSA rescoring, pkCSM-based ADMET prediction, and DFT calculations at the B3LYP/6-31G(d,p) level, with Tivantinib as the reference ligand.

Results and Discussion: Docking prioritized CPD1 (-10.31 kcal/mol) over Tivantinib (-9.09 kcal/mol). Molecular dynamics simulation indicated stable complexes, with CPD1-6QFQ showing a more compact, less solvent-exposed ensemble (Rg 1.42-1.45 nm; SASA 83-89 nm²; RMSD 0.09-0.15 nm). MM/GBSA favored CPD1 (ΔTOTAL -26.17 ± 2.79 kcal/mol) versus Tivantinib (-24.25 ± 4.50 kcal/mol). ADMET predicted high intestinal absorption for CPD1 (98.243%), a higher unbound fraction, and fewer liabilities (negative hepatotoxicity; negative hERG II inhibition). DFT supported CPD1 with a smaller ΔE (3.7165 eV) and higher softness (0.5381 eV⁻¹) than Tivantinib.

Conclusion: Convergent computational evidence nominates CPD1 as a leading putative Mcl-1 inhibitor for optimization, while target engagement, efficacy, and safety require experimental validation.

Graphical Abstract