VOLUME 18 (Supplement)

Philippine marine natural product scaffolds as inhibitors of DNA damage response pathways with promising binding propensity, stability, and pharmacokinetic profiles

Since identifying effective compounds is time-consuming and costly, computational drug-discovery methods now enable high-throughput screening of bioactive molecules. Philippine marine natural products (MNPs) were computationally screened against four targets in the DNA damage response (DDR) pathways: Poly (ADP-ribose) polymerase 1 (PARP-1), Histone Deacetylase 2 (HDAC2), and topoisomerases I and II (TOPOI and TOPOII). These targets are crucial in various diseases, including cancer. A total of 27 MNPs were screened through molecular docking. Most favorable complexes were further analyzed for pharmacokinetic and drug-likeness profiling, visualization and molecular interaction analysis, and molecular dynamics (MD) simulations. Several MNPs demonstrated strong binding affinities to DDR targets, along with promising pharmacokinetic profiles supporting their drug candidacy including Ningalin B for PARP-1; Perophoramidine for HDAC2; Ulithiacyclamide B for TOPOI; and Patellamide C for TOPOII. MD simulations affirmed the stability of the best complexes via root-mean-square deviation and fluctuation, radius of gyration, and interaction energy analyses. Overall, the in silico results highlight the potential of Philippine MNPs—especially Ningalin B, Perophoramidine, Ulithiacyclamide B, and Patellamide C—as natural-product inhibitors of DDR pathways relevant to anticancer drug discovery.