In the present study, solvent selection for extraction purpose was done on the basis of already available literature [
18]. Previous studies suggest that methanol and hot water are the ideal solvents for extraction of antioxidants and other endogenous compounds present in a plant [
19]. Thus, the extraction of plant material was done by a maceration process in absolute methanol to obtain the maximum content of chemical constituents. Various studies have suggested the role of plant extracts as α-glucosidase inhibitors clearly indicating the potential of these extracts to manage hyperglycemia [
20]. The activity of these plant extracts can be attributed to phytoconstituents present in them, such as flavonoids, alkaloids, terpenoids, anthocyanins, glycosides, phenolic compounds. In the present study, among all the methanolic plant extracts,
Cornus capitata Wall. extract explicated a remarkable inhibition potential (98.37% at 50 μg/mL) against the α-glucosidase enzyme. The other methanolic extracts were found to be less effective against the α-glucosidase enzyme. On the basis of activity shown by the crude methanolic extract of
Cornus capitata Wall., it was further fractionated successively in different polar and non-polar solvents [
15]. Among its fractions, ethyl acetate fraction showed the maximum inhibitory activity. Extraction of a type of compound depends upon the selection of the solvent. Ethyl acetate fraction is known to be rich in flavonoids [
17,
21]. Thus, enzyme inhibitory activity shown by ethyl acetate fraction can be attributed to its rich flavonoid contents. Critical analysis of the results obtained suggested that the methanolic crude extract of leaves of
Cornus capitata Wall. showed better activity than its all fractionates. The decrease in the enzyme inhibitory activity shown by different fractions may be due to the synergistic effect of the chemical constituents present in the crude methanolic extract. This suggests that the activity of crude methanolic extract of
Cornus capitata Wall. was due to the synergistic potential of chemical constituents present in it. Due to limited literature regarding the evaluation of antidiabetic activity of
Cornus capitata Wall., the information was gathered about other species of
Cornus. Various species of
Cornus have been reported in the literature for showing remarkable antidiabetic activity.
Cornus officinalis has been categorized as an important plant by the ministry of health of the People’s Republic of China and also declared as a valuable food supplement for the management of diabetes [
22]. Nearly 90% of the ancient Chinese herbal medicines contain
Cornus officinalis as an ingredient [
23]. It has been reported to contain iridoid glycoside and several other constituents in its crude extract responsible for showing remarkable α-glucosidase inhibitory effects in vitro and in vivo models [
24]
. Similarly,
Cornus mas (L.) also known as Cornelian cherry, is used in the preparation of beverages in European regions and used as an effective medicine for the treatment of Diabetes in Asia [
25]. Thus,
Cornus capitata leaves can also provide a possible medication for the better management of diabetes which has not been investigated yet.
To obtain further information regarding the type of inhibition, kinetic studies were carried out using a crude methanolic extract of
Cornus capitata Wall. It was observed that the slope and Km increased with the increasing concentration of the extract (inhibitor) but Vmax remained unaffected which indicated that
Cornus capitata Wall. methanolic extract inhibited the reaction to proceed through competitive interaction with the substrate. The mechanism involved in this type of inhibition includes either strong affinity or structural similarity to the substrate [
25,
26]. It can facilitate its binding with the active site of the enzyme, thus inhibiting the reaction to proceed forward. Therefore, to obtain useful information about the α-glucosidase enzyme inhibitory activity by methanolic extract of
Cornus capitata Wall., the lead regarding the chemical constituents present in it was taken from available literature [
6,
7]. However, very little attention has been paid to this plant. The literature was further explored to find the evidence supporting the antidiabetic activities of the constituents present in the crude methanolic extract of
Cornus capitata Wall. It was found that the pentacyclic triterpenoids such as arjunolic acid, betulinic acid, betulin, epibetulin, maslinic acid, and lupeol may be responsible for its antidiabetic activity [
27,
28]. Consequently, in order to understand the interactions between the protein 3WY1 (α-glucosidase enzyme homolog) and the constituents present in
Cornus capitata Wall. methanolic extract, docking studies were carried out. It revealed the significant binding efficiencies of the chemical constituents present in
Cornus capitata Wall., with binding pocket of protein (PDB ID: 3WY1) showing the consistent result with the in vitro findings, thus strengthening the basis of the remarkable α-glucosidase inhibitory potential of
Cornus capitata Wall. (Additional file
2: Figures S1-S7). Triterpenoids can act as lead molecules in the treatment of diabetes and its complications. Pentacyclic triterpenes such as betulinic acid, betulin, lupeol, maslinic acid etc. have been studied in both in vivo and in vitro models suggesting their potential in the treatment of diabetes and its complications [
28,
29]. Stability of a ligand in the binding pocket is calculated as minimum binding energy. Betulinic acid showed minimum binding energy i.e. 10.21 Kcal/mol followed by epibetulin, arjunolic acid, maslinic acid, lupeol, and betulin. Their significant α-glucosidase inhibitory effect may be due to the main triterpene nucleus and hydroxyl groups at R1 and R2 positions (Additional file
2: Figure S8). It favors hydrogen bonding and electrostatic interactions between the binding pocket of enzyme and hydroxyl groups. Carboxyl group at R3 position favors activity potential in pentacyclic triterpenes [
30]. Several studies support the potential of betulinic acid as an effective α-glucosidase inhibitor with IC
50 varying from 7.6–14.9 μM [
31,
32]. This activity can be due to hydroxyl group attached at R2 position (electron-donating group) and a carboxyl group attached. Further, replacement of hydroxyl group with carbonyl groups directly affect the inhibitory potential of pentacyclic triterpenes as in case of epibetulin. Additional hydroxyl group present other than R1 and R2 position in case of arjunolic acid decreased its inhibitory potential based on structure-activity relationship [
31]. Low inhibitory potential of betulin, when compared to its derivative, betulinic acid indicated the importance of carboxylic group [
33,
34]. Decreased activity of lupeol and absence of carboxylic acid in its structure can also be co-related. Maslinic acid is hydrophobic in nature with a rigid skeleton which results in its decreased bioavailability. However, its glycosylation at R2 and R3 position increase its inhibitory potential [
35]. Also, molecular shape and size of a compound decide easy penetration in the binding pockets followed by its interactions. Substituent groups and their positions in case of pentacyclic triterpenoids plays a very crucial role. Thus,
Cornus capitata Wall. can be used as an effective drug for the treatment and prevention of diabetes.