Poly(ADP-ribose)polymerases (PARPs) family consists of 18 members that play pivotal roles in many cellular processes, including DNA damage repair, gene expression, transcriptional modulation and programmed cell death pathway [1]. As shown in Fig. 1A, PARP1, the most prominent member of this family, comprises three independent domains: the DNA-binding domain (DBD), the automodification domain (AMD) and the C-terminal catalytic domain (CAT) [[2], [3], [4]]. The DBD includes two zinc fingers (ZF) domains (ZnⅠ, ZnⅡ) that recognize the structure of damaged DNA (Fig. 1B), one characteristic ZF domain (ZnⅢ) for inter-domain contact, and a nuclear localization signal (NLS) at the N-terminal of PARP1, ensuring proper subcellular targeting [5,6]. The AMD contains a phosphopeptide-binding C-terminal BRCA1 (BRCT) motif, which provides auto poly-ADP ribosylation (PARylation) sites and regulate protein-protein interactions. Additionally, the AMD included a tryptophan-glycine-arginine rich (WGR) domain that binds DNA to the ZF domain [7,8]. The CAT domain contains a site that binds the active NAD and a core catalytic site, which contains helical domain (HD), and the ADP-ribosyl transferase domain (ART) involved in catalysis and binding of nicotinamide adenine dinucleotide (NAD+) [9,10]. Moreover, the catalytic pockets of PARP1 were characterized by three sites: the nicotinamide-ribose binding (NI) site, the phosphate-binding (PH) site and the AD site, all of which are occupied by the substrate NAD+ [[11], [12], [13]].

As depicted in Fig. 1B, PARP1 is the most critical member of the PARP family, playing a pivotal role in responding to DNA single-strand breaks (SSBs) via the base excision repair (BER) pathway and to DNA double-strand breaks (DSBs) through homologous recombination (HR) and non-homologous end joining (NHEJ) pathways [[14], [15], [16], [17]]. When the DNA damage response (DDR) is triggered, PARP1 recognizes the damage area through its ZF domains and binds to the site of break. This binding induces a conformational change in the HD, thereby activating PARP1 [[18], [19], [20]]. Upon activation, PARP1 consumes NAD+, which is cleaved into ADP-ribose and nicotinamide. This process generates PARylation, which serves as a docking site for DNA repair factors, guiding them to the damaged DNA region. Once these repair factors are in place, the DNA strand is repaired, and the cell survive [[21], [22], [23]].

PARP inhibitors are compounds designed to block PARP activity. Their structural design is based on nicotinamide, a product of PARP1-catalyzed NAD+ decomposition [24]. Key structural features of PARP inhibitors include an electron-rich aromatic ring, hydrogen bond acceptor and donor, and at least one active hydrogen on the amide bond which are essential for their activity [9]. These inhibitors competitively bind to the NI site of PARP, thereby inhibiting DNA damage repair and ultimately leading to the accumulation of DSBs [25]. As illustrated in Fig. 2A, the FDA has approved several PARP inhibitors, such as Olaparib, Niraparib, Talazoparib and Rucaparib, for the treatment of various cancers, including breast cancer, ovarian cancer, peritoneal cancer and other diseases [[26], [27], [28], [29]]. The structural analysis of the existing PARP1 inhibitors indicated that their key binding fragments can be roughly divided into benzimidazole carboxamide, phthalazinone, and tricyclic indole lactams. Most of the existing PARP1 inhibitors retain these three core structures or derivative structures.

Moreover, some natural product derivatives have been proved to have good PARP1 inhibitory activity (Fig. 2B). The apigenin-piperazine hybrid 15l has good antitumor activity and PARP1 selectivity [30], erythrina derivatives 10b and homoerythrina alkaloid derivatives 10n have also been shown to induce tumor cell apoptosis as PARP1 inhibitors [31,32]. These natural products provide new selective structures for PARP1 inhibitors.

Natural products are the most important sources of anticancer drugs. In fact, approximately 50 % of the anti-tumor drugs currently in use are either directly or indirectly derived from natural products [33,34]. In recent years, a diverse array of compounds has emerged as significant players in the field of anti-tumor research. For instance, the phenolic compound curcumin has been shown to inhibit tumor angiogenesis by suppressing endothelial cell proliferation and integrin expression [35]. Additionally, PARP1-targeted 5H-dibenzo[b,e]azepine-6,11-dione derivatives have demonstrated notable efficacy in inhibiting the cell proliferation of lung cancer cells [36]. Polysaccharides, such as Lycium barbarum polysaccharides (LBP), are also gaining attention for the potential to inhibit tumor growth and contribute to cancer treatment and prevention through the induction of tumor cell apoptosis [37]. Collectively, these findings underscore the crucial role that natural products play in cancer therapy and highlight their promise as a rich source for the design of novel anti-tumor drugs.

Coixol (6-methoxy-2(3H)-benzoxazolone), a polyphenolic compound derived from Coix seed, has garnered interest across various fields, including cosmetics, food, and pharmaceuticals [38]. Recent studies have revealed that coixol can protect against acute kidney injury by reducing cell senescence and minimizing tissue damage [39]. Another investigation focused on modifying coixol to assess its impact on inflammatory factors. The results indicated that coixol derivatives could significantly downregulate the expression of iNOS and inhibit the production of NO by modulating the LPS-induced NF-κB signaling pathway, thereby exhibiting substantial anti-inflammatory activity [40]. Moreover, emerging research has suggested that coixol possesses anticancer properties, although its precise molecular targets have yet to be fully elucidated [41,42]. Given these promising findings, coixol holds considerable potential as a candidate for the development of novel anticancer therapies.

Drug development is a challenging, time-consuming, and costly endeavor. However, with advancements in technology, computer-aided drug design (CADD) has emerged as a highly effective tool in the field of pharmaceutical research. CADD is widely utilized in the development of various drugs, significantly reducing both the time and expense associated with traditional drug discovery processes [43,44]. By leveraging computational power, CADD enables the design of drug molecules with optimal structures through the simulation of interactions between target proteins and potential ligands [45]. Currently, there is a notable scarcity of PARP1 inhibitors derived from natural products. Given the vast potential of natural products as a source of novel therapeutic agents, we aim to leverage CADD technology to develop a PARP1 inhibitor based on natural products. Our goal is to identify and design a compound with a novel core skeleton structure, thereby expanding the repertoire of effective PARP1 inhibitors and potentially offering new therapeutic options for the treatment of diseases where PARP1 plays a crucial role.