Exploring the Interaction between 27 Pyrimidinone Derivatives and XIAP through Theoretical Modeling

For many years, various drugs have been utilized to treat different cancer types, but some of these treatments come with adverse effects such as liver damage, hypertension, and erectile dysfunction. In the pursuit of alternative therapeutic options, several new compounds have been developed to address this clinical challenge. Yet, the interactions of these compounds with biomolecules involved in cancer development remain largely unclear. With this context in mind, the present study aimed to explore the potential theoretical interaction of a series of pyrimidinone derivatives (compounds 1-27) with the X-linked inhibitor of apoptosis protein (XIAP), a key player in cancer progression, using the Docking model. The findings indicated that certain pyrimidinone derivatives (compounds 1-6, 10, 11, 14, 15, 22-24, 26, and 27) exhibited the ability to bind with the surface of the XIAP protein. In conclusion, these results suggest that some pyrimidinone derivatives may modulate XIAP’s biological activity, making them promising candidates for cancer therapy.

Cancer continues to be one of the leading causes of death globally, contributing significantly to reduced life expectancy across populations [1-9]. This disease is on the rise in both developed and developing nations, driven by factors such as aging and population growth [10-13]. Moreover, certain molecular signaling pathways have been found to play crucial roles in cancer progression. For instance, research has shown that the X-linked inhibitor of apoptosis protein (XIAP) can modulate cell death pathways by binding to and inhibiting caspases [14-16]. Further studies suggest that XIAP may be implicated in the onset and development of various cancer types [17-23]. In response to these findings, several therapeutic agents have been developed. One such agent, Clioquinol (5-chloro-7-iodo-8-quinolinol), has been shown to induce cytoplasmic XIAP clearance, thereby reducing prostate cancer [24]. Another compound, (3S,6S,9R,10aR)-6-((S)-2-(Methylamino)propanamido)-5-oxo 9-(2-phenylacetami-do)-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo [1,2-a]azocine-3-carboxamide, inhibits cancer cell growth (MDA-MB-231) through XIAP suppression [25]. Additionally, the synthesis of benzodiazepinones as selective XIAP inhibitors for cancer therapy has been explored using in vitro models [26]. Furthermore, studies on human gastric cancer cell lines, including AGS (adenocarcinoma), KATO-III (signet-ring cell carcinoma), and NCI-N87 (gastric carcinoma), have demonstrated that Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) reduces XIAP expression, leading to cell cycle arrest and apoptosis in the S and G2/M phases [27]. Embelin has also shown XIAP inhibitory activity in human prostate cancer cell lines (PC-3, LNCap, CL-1, DU-145) [27]. Additionally, certain diazabicyclic derivatives have been reported to inhibit XIAP expression in cancer cell lines like MDA-MB-231 and SK-OV-3 [28]. These findings suggest that various drugs can downregulate XIAP expression, thereby affecting cancer cell proliferation. However, there is limited research on the interaction between pyrimidinone derivatives and XIAP.

This knowledge gap may stem from the varied experimental designs that focus on different molecular mechanisms of cancer. Therefore, this study aimed to investigate the potential interaction between twenty-seven pyrimidinone derivatives and XIAP using a theoretical model.

In this study, a group of 27 pyrimidinone derivatives, previously identified in PubChem [29], was chosen to investigate their possible interactions with the X-linked inhibitor of apoptosis protein (XIAP). The methodology for evaluating these interactions is described as follows:

Ligand-protein interaction analysis

To examine the potential interaction between twenty-seven pyrimidinone derivatives and the X-linked inhibitor of apoptosis protein (XIAP), the 4ic2 protein [32] was utilized as a theoretical model. For comparison, compounds A, B, and C, known XIAP inhibitors [25, 30, 31], were included. The binding energies corresponding to the interactions between the pyrimidinone derivatives and the 4ic2 protein were calculated using the DockingServer software [33].

Pharmacokinetic evaluation

The pharmacokinetic parameters of the pyrimidinone derivatives were evaluated using the SwissADME tool [34].

Toxicity assessment

The potential toxicity of pyrimidinone derivatives (compounds 2, 5, 9, 11, 13, and 15) was assessed using the GUSAR software [35].

Research in the literature has demonstrated that certain compounds can alter XIAP’s biological activity [24-27], which results in reduced growth of cancer cells. However, the interaction between pyrimidinone derivatives and XIAP remains underexplored, leaving limited insight into how these compounds might affect cancer cell behavior.

Interaction between protein and ligands

This research aimed to investigate the binding of 27 pyrimidinone derivatives to XIAP using the 4ic2 protein and control compounds A, B, and C (Figure 1) in a docking framework [33]. As shown in Table 1 and Figures 2 and 3, various amino acid residues play a role in the binding of pyrimidinone derivatives with XIAP. These findings suggest that the interaction is influenced by the distinct functional groups present in the pyrimidinone derivatives (Table 1; Figures 2 and 3).

Binding energy analysis

It has been reported that the interaction between ligands and proteins is influenced by various energy components, including binding free energy, electrostatic forces, total intermolecular energy, and Van der Waals interactions [34]. In this study, we assessed the thermodynamic factors associated with the binding of pyrimidinone derivatives to the 4ic2 protein surface, using compounds A, B, and C as controls. Our results indicated notable differences in the energy metrics between the pyrimidinone derivatives and the 4ic2 protein surface compared with the control compounds (Table 2). Moreover, the inhibition constant (Ki) for pyrimidinone derivatives 2, 3, 4, 6, 22, 24, and 26 was found to be lower than the corresponding values for the controls (A, B, and C). Additionally, pyrimidinone derivatives 1, 5, 10, 11, 14, 15, 23, and 27 exhibited lower Ki values compared to controls A and C. These findings suggest that certain pyrimidinone derivatives (1-6, 10, 11, 14, 15, 22-24, 25, and 27) may inhibit XIAP’s biological functions, potentially reducing prostate cancer progression.

I = free energy of binding (kcal/mol); II = inhibition constant, Ki (mM); III = Vander Waals forces + H-bond + desolv energy (kcal/mol); IV = electrostatic energy (kcal/mol); V = total intermolecular energy (kcal/mol); VI = interaction Surface

Pharmacokinetic evaluation

Several approaches are described in the literature for predicting drug pharmacokinetic parameters, including PK/PD, MONOLIX, CXTMAIN, and SwissADME [36-39]. In this study, the pharmacokinetic properties of pyrimidinone derivatives were assessed using the SwissADME tool (Table 3). The results indicated notable differences in the gastrointestinal absorption and metabolic processes—specifically, the involvement of various cytochrome P450 enzymes—when compared to the control compounds. This suggests that their structural composition may influence the pharmacokinetics of pyrimidinone derivatives.

Toxicity assessment

Existing literature highlights the potential toxicity of various pyrimidinone derivatives across different biological models [40-43]. Based on these findings, the toxicity of specific pyrimidinone derivatives (2, 5, 9, 11, 13, and 15) was assessed using the GUSAR software [35]. The analysis revealed that the control compounds A, B, and C exhibited higher lethal doses (LD50) upon intraperitoneal administration than the pyrimidinone derivatives. However, when administered via intravenous, oral, and subcutaneous routes, pyrimidinone derivatives displayed varying degrees of toxicity compared to the controls. These findings imply that the dose and method of administration of each pyrimidinone derivative may influence its toxicity profile (Table 4).

IP = intraperitoneal; IV = intravenous; Oral = oral;  SC = subcutaneous.

The results from the theoretical examination of the interaction between pyrimidinone derivatives and the 4ic2 protein reveal that derivatives 1-6, 10, 11, 14, 15, 22-24, 26, and 27 appear to exhibit a stronger binding affinity for XIAP, leading to a higher potential for XIAP inhibition when compared to the control compounds. Based on these observations, these pyrimidinone derivatives could serve as promising candidates for cancer treatment through their XIAP-inhibitory activity.

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This research was conducted in accordance with the ethical guidelines of the pharmacochemical research laboratory at the Autonomous University of Campeche.

Fatima Zahra Amrani & Youssef Benali contributed to this work.

Authors and affiliations

Department of Drug Development and Clinical Toxicology, Faculty of Sciences, Mohammed V University, Rabat, Morocco
Fatima Zahra Amrani & Youssef Benali

Corresponding author

Correspondence to Fatima Zahra Amrani

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