DOI: 10.6084/m9.figshare.30884642
title: <b>Systematic Analysis of Chemical Constituents, Pharmacokinetic Properties, and Toxicity Risks of </b><i>Lithocarpus litseifolius (Hance) Chun</i><b>: A Computational Study</b>

description: <b>Abstract</b><b>Objective:</b> <i>Lithocarpus litseifolius (Hance) Chun</i> is a valuable medicinal and edible plant with multiple pharmacological activities. This study systematically reviews its chemical constituents and evaluates their drug-likeness, pharmacokinetic properties, and toxicity risks to provide evidence for its application and development.<b>Methods: </b>A comprehensive literature search was performed using the keyword "<i>Lithocarpus litseifolius (Hance) Chun</i>" to identify flavonoids, polyphenols, and triterpenoids. The Simplified Molecular Input Line Entry System (SMILES) structures were retrieved from PubChem. Pharmacokinetic parameters were predicted using SwissADME, including Lipinski's rule of five, ESOL solubility, oral bioavailability (BA), gastrointestinal (GI) absorption, log skin permeability coefficient (log Kp), and P-glycoprotein substrate (P-gp S) status. PAINS and Brenk structural alerts were assessed for toxicity screening. Target prediction was conducted using SwissTargetPrediction (Homo sapiens, probability &gt; 0).<b>Results: </b>A total of 40 flavonoids, 6 polyphenols, and 14 triterpenoids were identified. After excluding compounds without explicit SMILES structures, 34 flavonoids, 6 polyphenols, and 8 triterpenoids were retained for analysis. Among these 48 compounds, 23 satisfied the criteria of violating ≤ 1 Lipinski rule and having BA ≥ 30%. Additionally, 22 compounds (45.8%) had neither PAINS nor Brenk alerts, while 12 compounds (25.0%) exhibited both alerts, with 3 compounds containing ≥ 2 Brenk fragments.<b>Conclusion: </b><i>L. litseifolius</i> demonstrates favorable drug-likeness and low toxicity risk. However, compounds with dual PAINS/Brenk alerts require structural optimization or exclusion. This computational analysis provides a foundation for further pharmacological development and clinical application of L. litseifolius constituents.<b>Keywords: </b>Lithocarpus litseifolius; flavonoids; polyphenols; triterpenoids; drug-likeness; SwissADME; toxicity assessment; bioavailability<b>Background</b><i>Lithocarpus litseifolius (Hance) Chun</i>, also known as Lithocarpus litseifolius or sweet tea, is a plant belonging to the genus Lithocarpus in the family Fagaceae of the order Fagales [1]. It is a "medicinal and edible" resource in southern China, with provenances from Guangxi exhibiting superior quality compared to those from other regions [2]. As a precious plant integrating three functions—tea, sweetener, and medicine—its medicinal value has gradually attracted attention [3]. In 2017, it was approved as a "new food raw material" at the national level, and in 2024, it was included in the Guangxi characteristic food and medicine catalog.<i> L. litseifolius</i> contains various bioactive constituents, such as flavonoids [4], phenolic glycosides [5], and triterpenoids [6]. Studies have shown [6, 7] that these components possess multiple biological activities, including antioxidant, anti-inflammatory, hypoglycemic, hypolipidemic, uric acid-lowering, and antitumor effects. This study aims to systematically review its main chemical constituents to provide evidential support for the application of L. litseifolius.<b>1 Methods</b><b>1.1 Screening of Active Constituents from L. litseifolius</b>A literature search was conducted using the keyword "<i>Lithocarpus litseifolius (Hance) Chun</i>" to identify flavonoids, phenolic compounds, and triterpenoids. The Simplified Molecular Input Line Entry System (SMILES) of these compounds were then retrieved from the PubChem database. The SwissADME database (http://www.swissadme.ch/) was used to predict whether the compounds complied with Lipinski's rule of five (molecular weight [MW] ≤ 500, lipophilicity [logP] ≤ 5, ≤ 10 hydrogen bond acceptors, ≤ 5 hydrogen bond donors). Additionally, key pharmacokinetic parameters were summarized and evaluated, including ESOL solubility (mg/ml) ≥ 0.01, oral bioavailability (BA) ≥ 30%, gastrointestinal (GI) absorption: HIGH, log skin permeability coefficient (log Kp [cm/s]), and P-glycoprotein substrate (P-gp S) status [8, 9]. "PAINS" and "Brenk" alerts [10] were also assessed to identify potential nonspecific bioactivity interference, toxicity risks, or chemical instability, providing structural alerts for early toxicological screening.<b>1.2 Target Prediction of Active Constituents from L. litseifolius</b>Compound target prediction was performed using the SwissTargetPrediction database (http://www.swisstargetprediction.ch/), with the species restricted to Homo sapiens and probability &gt; 0 [11]. After data organization and deduplication, the pharmacological characteristics and targets of L. litseifolius were obtained.<b>2 Results</b>A systematic literature review was conducted to comprehensively compile compounds from <i>L. litseifolius</i>. The results revealed a total of 40 flavonoid components; however, explicit SMILES structures could not be retrieved from the PubChem database for 6 of them. Additionally, 6 polyphenolic compounds and 14 triterpenoid compounds were identified, of which 5 triterpenoids yielded undefined results and 1 triterpenoid lacked a clear SMILES structure in PubChem. Based on these findings, constituents without definite SMILES structures were excluded, finally retaining 34 flavonoids, 6 polyphenols, and 8 triterpenoids.Regarding the pharmacological properties of <i>L. litseifolius</i>, 33 compounds had a molecular weight ≤ 500; 22 compounds had ≤ 10 hydrogen bond acceptors; 25 compounds had ≤ 5 hydrogen bond donors; 39 compounds had a lipophilicity (logP) ≤ 5; 23 compounds violated ≤ 1 Lipinski rule; 37 compounds had ESOL solubility &gt; 0.01 mg/ml; 23 compounds had BA ≥ 30%; 11 compounds exhibited HIGH gastrointestinal absorption; 0 compounds had positive log skin permeability coefficient (log Kp [cm/s]); and 27 compounds were identified as P-gp substrates (detailed data are available in the table).In terms of potential activity interference, toxicity risks, or chemical instability of<i> L. litseifolius</i> constituents, 45.8% of compounds (22/48) had neither PAINS nor Brenk alerts, while 75.0% of compounds (36/48) had no PAINS or Brenk alerts. Conversely, 25% of compounds (12/48) exhibited both PAINS and Brenk alerts, and 3 compounds contained ≥ 2 Brenk fragments.<b>3 Discussion</b><b>Analysis of Pharmacological Properties, Toxicity Risks, and Administration Routes</b>Pharmacological property analysis demonstrated that<i> L. litseifolius</i> exhibits favorable drug-likeness and high bioavailability. ESOL solubility indicated that some compounds are suitable for oral administration. However, only 11 compounds showed HIGH gastrointestinal absorption, which may limit the bioavailability of certain constituents. Nevertheless, solubility can be enhanced using techniques such as micronization and nanocrystallization, solid dispersions, surfactants, and cosolvents [12]. The log skin permeability coefficient (log Kp) values were all negative, indicating weak transdermal penetration capacity. If transdermal administration is considered, penetration enhancers such as borneol, menthol, and camphor [13] should be added to improve percutaneous absorption and thereby enhance local or systemic therapeutic effects.Toxicity risk analysis revealed that<i> L. litseifolius </i>possesses high structural reliability and low toxicity risk. However, 25% of compounds exhibited both PAINS and Brenk alerts, and 3 compounds contained ≥ 2 Brenk fragments, classifying them as high-risk candidates that should be prioritized for exclusion or structural modification. Future research should further explore the pharmacological and toxicological properties of these compounds and optimize their structures to meet clinical application requirements.<b>References</b>[1] He WW, Huang A, Tang XY, et al. Research progress on chemical constituents, pharmacological effects, and quality evaluation of Lithocarpus litseifolius [J]. Central South Pharmacy, 2022, 20(11): 2648-2657.[2] Wang K, Huang XL, Li BC, et al. Analysis and evaluation of main economic traits and active components in 30 provenances of Lithocarpus polystachyus [J]. Southwest China Journal of Agricultural Sciences, 2019, 32(05): 1051-1056.[3] Lin XQ, Wang QS, Qin XH, et al. Textual research on sweet tea "Lithocarpus litseifolius" in materia medica [J]. Journal of Fujian Agriculture and Forestry University (Natural Science Edition), 2023, 52(06): 785-792.[4] Xu J, Zhao Y, Wen J, et al. Composition and toxicity of total water-soluble flavonoids from Lithocarpus litseifolius (Hance) Chun (sweet tea) [J]. Food and Agricultural Immunology, 2024, 35(1).[5] Wang M, Liu X, Zhang Z, et al. Phytochemicals and bioactive analysis of different sweet tea (Lithocarpus litseifolius [Hance] Chun) varieties [J]. Journal of Food Biochemistry, 2021, 45(3): e13183.[6] Cheng Y, Liu F, Wang C, et al. Bioactive Triterpenoids from the Leaves and Twigs of Lithocarpus litseifolius and L. corneus [J]. Planta Medica, 2018, 84(1): 49-58.[7] Wei YQ, Cai YL, Yang Y, et al. Research progress on dihydrochalcones from Lithocarpus litseifolius extracts in treatment of type 2 diabetes mellitus and its complications [J]. Chinese Journal of Chinese Materia Medica, 2025, 50(3): 658-671.[8] Avdeef A. Prediction of aqueous intrinsic solubility of druglike molecules using Random Forest regression trained with Wiki-pS0 database [J]. ADMET DMPK, 2020, 8(1): 29-77.[9] Pillai O, Dhanikula AB, Panchagnula R. Drug delivery: an odyssey of 100 years [J]. Current Opinion in Chemical Biology, 2001, 5(4): 439-446.[10] Rani N, Kumar P. Exploring Natural Compounds as Potential CDK4 Inhibitors for Therapeutic Intervention in Neurodegenerative Diseases through Computational Analysis [J]. Molecular Biotechnology, 2025, 67(8): 3310-3329.[11] Zhong T, Sun J, Miao M, et al. 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