Abstract

Introduction: Natural products remain the best source of novel agents for effective drug development. This study aimed to isolate and identify compounds from Synclisia scabrida (Miers) ex Oliv and to evaluate their anticancer potential by in vitro cytotoxicity and in silico studies. Methods: The isolated compounds were identified using spectroscopic methods, and their anticancer activities were evaluated using MTT assay. Furthermore, binding of the compounds to their potential molecular targets were determined via in silico computer modeling approach. Results: Two compounds were identified and found to be new bisbenzylisoquinoline (BBIQ) alkaloids: SS_C2 (a cosculine analogue) and SS_C4 (a cycleanine analogue). Both were selectively toxic towards HCT-116 (colon cancer) and MCF-7 (breast cancer) cells, respectively. The selectivity was far greater than that of gemcitabine, which showed higher toxicity to normal lung cells (BEAS-2B). Compared with the docked poses of the two ligands, SS_C2 and SS_C4, the simulation trajectories showed that the complexed ligands underwent slight conformational changes that resulted in stronger interactions with PARP1. The main interactions common to the two ligands that are likely to be responsible for the stable binding are electrostatic interactions between the ionised amines and the carboxylate groups of Asp105 and Asp109, a pi-pi stacking interaction with Tyr246, and a pi-pi stacking or pi-alkyl interaction with His201. Those interactions were maintained throughout the simulation time, and there were other intermittent interactions including hydrogen bonding and other hydrophobic interactions. The in silico simulation results showed very high PARP1–ligand complex stability for both compounds. Conclusion: SS_C2 and SS_C4 are new potential PARP1 inhibitors, which in turn provide a plausible explanation of their observed anticancer activities.

Keyword: Synclisia scabrida, Isolation, Structural elucidation, In silico studies, Cytotoxicity, PARP1 inhibitor