Abstract

   Archidendron clypearia (A. clypearia), a Fabaceae family member, is
   widely used as an anti-inflammatory herbal medicine; however, its
   antibacterial and antidiabetic properties have not been extensively
   investigated. This study aimed to systematically analyze the
   antibacterial and antidiabetic components of A. clypearia by utilizing
   a combination of analytical methods. First, ten different polarity
   extracts were analyzed through ultra-performance liquid chromatography
   (UPLC), and their antibacterial and antidiabetic activities were
   evaluated. Then the spectrum–effect relationship between the biological
   activity and UPLC chromatograms was analyzed by partial least squares
   regression and gray relational analysis, followed by corresponding
   validation using isolated components. Finally, network pharmacology and
   molecular docking were implemented to predict the main antibacterial
   target components of A. clypearia and the enzyme inhibition active
   sites of α-amylase and α-glucosidase. P15, P16, and P20 were found to
   be the antibacterial and antidiabetic active components. The inhibitory
   effect of 7-O-galloyltricetiflavan (P15) on six bacterial species may
   be mediated through the lipid and atherosclerosis pathway, prostate
   cancer, adherens junctions, and targets such as SRC, MAPK1, and AKT1.
   The molecular docking results revealed that 7-O-galloyltricetiflavan
   and 7,4′-di-O-galloyltricetiflavan (P16/P20) can bind to α-amylase and
   α-glucosidase pockets with binding energies lower than −6 kcal/mol. Our
   study provides guidance for the development of antibacterial and
   antidiabetic products based on A. clypearia and can be used as a
   reference for the evaluation of bioactivity of other herbs.

   Keywords: Archidendron clypearia, spectrum–effect relationship,
   antibacterial, antidiabetic, network pharmacology, molecular docking

1. Introduction

   Archidendron clypearia (Jack.) Nielsen (A. clypearia), a member of the
   Fabaceae family, has been widely used as a traditional medicine for
   detoxification, cooling, and edema reduction in Southeast Asia because
   it is composed of abundant polyphenols [[38]1]. The Chinese folklore
   book “Lu Chuan Ben Cao” records the use of A. clypearia for the
   treatment of burns and ulcers since the 17th century. Moreover, A.
   clypearia is reported to have various effects, including
   anti-inflammatory, antioxidant, antibacterial, and antidiabetic
   effects. However, its exploitation is mostly based on its overall
   extract, and the specific efficacy of the components of A. clypearia
   has not been extensively investigated.

   Salmonella, Bacillus subtilis, Klebsiella pneumoniae, Staphylococcus
   aureus, Escherichia coli and Pseudomonas aeruginosa are common
   pathogens that cause diseases such as diarrhea, fever, and pneumonia,
   and can even endanger human life [[39]2]. A. clypearia is rich in
   polyphenols that have been widely demonstrated to have antibacterial
   effects. The common antibacterial mechanisms of polyphenols mainly
   include cell wall disruption, alteration of cell membrane permeability,
   cell metabolism changes, and DNA synthesis disruption [[40]3]. The
   effects of different components of polyphenols on different pathogenic
   bacteria also vary greatly. Thus, the search for highly active
   polyphenolic components is significant for promoting the development of
   antibacterial products.

   Diabetes mellitus (DM) is a group of clinical syndromes caused by the
   interaction of genetic and environmental factors. While DM has a
   complex etiology, it is closely related to the dysregulation of
   α-glucosidase and α-amylase activity, and the determination of the
   inhibitory activity of drugs toward these two enzymes is an important
   indicator of their hypoglycemic ability [[41]4]. Although traditional
   antidiabetic drugs such as acarbose and metformin are highly effective,
   they have various side effects including flatulence, indigestion and
   other gastrointestinal reactions, whereas many herbal medicines have
   low toxicity and a wide range of efficacy. Therefore, novel
   antidiabetic drugs based on herbal medicines can be used to overcome
   the limitations of the current antidiabetic drugs, provide a more
   diverse choice of treatments, and improve the standard of living of
   diabetic patients ([42]Figure 1).

Figure 1.

   [43]Figure 1
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   Correlation between A. clypearia and the selected targets.

   The traditional method for screening active substances in natural
   products is multistep extraction and separation using organic solvents
   followed by activity determination. However, this method is
   time-consuming, labor-intensive, environmentally unfriendly, and
   inefficient. Spectrum–effect relationship analysis is a method for
   determining active ingredients by correlating the content of the
   product in the spectrum of the research object with their bioactivity
   via chemometrics [[45]5]. Spectrum–effect relationship analysis can be
   carried out on different extracts or extraction sites of the same herb.
   Spectrum–effect relationship analysis has been widely used in the
   discovery for active ingredients of various herbal medicines.

   Network pharmacology was first proposed by Hopkins in 2007 [[46]6]. It
   is based on the theory of systems biology and integrates the techniques
   of multiple disciplines such as multidirectional pharmacology,
   bioinformatics, and computer science to construct a multilevel
   “disease–target–drug” network in order to explore the correlation
   between drugs and diseases and elucidate the mechanism of drug action.
   Network pharmacology has holistic and systematic characteristics that
   overlap with the multicomponent and multi-action characteristics of
   Chinese herbal ingredients. Currently, the mechanism of the active
   components of A. clypearia is poorly understood. We used a combination
   of network pharmacology and spectrum–effect relationship analysis to
   construct a “component–target–disease” network for determining the
   potential active components of A. clypearia, employing tools such as
   topological parameter analysis, visualization of protein interaction
   network diagrams, histograms, bubble diagrams, and drug action on
   target sites to predict the mechanism of action.

   Molecular docking is the process of finding the optimal binding mode
   between small molecules (ligands) and biomolecules (receptors) by
   simulating the geometric and energetic matching of molecules through
   chemometric methods, and includes the rigid, semi-flexible, and
   flexible docking methods. Molecular docking can be used to simulate the
   binding site between a drug molecule and its corresponding ligand and
   to assess its energy of action; it is beneficial for guiding drug
   development and elucidating the mechanism of action of a drug [[47]7].

   In this study, the main components of 70% aqueous ethanol (EtOH)
   extracts of A. clypearia were identified, and the spectrum–effect
   relationship between the biological activity and UPLC chromatograms was
   analyzed through partial least squares regression (PLSR) and gray
   relational analysis (GRA). The screening results were validated through
   pharmacological activity testing of isolated compounds. The mechanism
   of action of the screened antibacterial substances was also predicted
   and evaluated by network pharmacology. Furthermore, the enzyme
   inhibition active sites of α-amylase and α-glucosidase were analyzed by
   molecular docking. The combination of multiple analytical methods
   including spectrum–effect relationship analysis, network pharmacology,
   and molecular docking allows the exploitation of the medicinal value of
   A. clypearia ([48]Figure 2).

Figure 2.

   [49]Figure 2
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   Strategy for studying the antibacterial and antidiabetic components
   extracted from A. clypearia.

2. Results and Discussion

2.1. Characterization of A. clypearia

   The S1 extract was analyzed by mass spectroscopy. Based on the relative
   retention time, mass-to-charge ratio (m/z), number of fragment ions,
   and literature references, the components of A. clypearia were