Abstract
BACKGROUND: Reactivating the apoptosis pathway in cancer cells represents a crucial therapeutic strategy for cancer treatment, as malignant cells often evade apoptosis to sustain uncontrolled proliferation. Among the anti-apoptotic proteins, Bcl-xL has been implicated in the pathogenesis of various cancers due to its overexpression. Inhibition of this protein has therefore emerged as a key target for several FDA-approved anticancer drugs. In recent decades, research on natural compounds has increasingly shifted toward molecular-level understanding, facilitating the development of potent anticancer agents. One medicinal plant of interest is Andrographis paniculata (Burm.f.) Wall. ex Nees, which has shown a wide range of pharmacological activities, including potential anticancer properties. METHODS: In this study, we curated a set of previously identified natural compounds from A. paniculata in LOTUS database that target Bcl-xL inhibition by in silico methods, included molecular docking and molecular dynamics simulation. RESULTS: Our findings reveal three compounds exhibiting strong binding affinity toward the Bcl-xL protein. In silico analysis of their anticancer properties suggests that these compounds possess high potential as TP53 enhancers, anticarcinogenic, antineoplastic, apoptosis agonists, antimetastatic, cytostatic, antioxidant agents, and Myc inhibitors. Moreover, all three compounds conform to Lipinski's rule of five and show favorable drug-likeness characteristics. Molecular dynamics simulations over 100 ns, coupled with in-depth principal component analysis and binding free energy calculations, further support the stable and strong interactions of these compounds within the Bcl-xL active site. CONCLUSIONS: Natural compounds from A. paniculata, particularly andrographolide derivatives, exhibit stable and strong interactions with the Bcl-xL protein and possess multiple predicted anticancer activities. These findings support their potential as lead molecules for the development of Bcl-xL-targeted anticancer therapeutics.