Computational design of quinazolin-4(3H)-one derivatives as multitarget inhibitors against angiogenesis and metabolic reprogramming to help overcome cancer resistance

Dysfunction of receptor tyrosine kinases (RTKs) in angiogenesis significantly contributes to cancer progression. However, inhibiting primary angiogenesis pathways often leads to acquired resistance through various mechanisms, including alternative pathways. Targeting both angiogenesis and tumor energy metabolism, particularly via RTKs and phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3), presents a promising strategy to slow tumor growth and propagation. The present study explored Quinazolin-4(3H)-one derivatives as kinase inhibitors using 3D-QSAR modeling to design more effective compounds. The developed CoMSIA/SHA model demonstrated high reliability, indicated by a determination coefficient (R
2
= 0.995) and Leave-One-Out cross-validation coefficient (Q
2
= 0.717). The model’s robustness and stability were further demonstrated by external validation (R
2
Pred
= 0.832). Fifty-nine newly designed compounds with potent inhibitory activity were generated, with absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening validating their favorable profiles. Compared to the most active molecule (
molecule 39
) in the dataset and the reference drug for each protein target, molecular docking revealed that four newly designed compounds exhibited better binding affinity (−8.5 to −11.5 kcal/mol) toward RTKs and PFKFB3. Molecular dynamics simulations confirmed the stability of these compounds in the binding pockets for 100 ns. In addition, the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) band gap energies and the molecular electrostatic potential (MEP) surface indicated that the four proposed compounds possessed favorable electronic properties, positioning them as good candidates for drug design.