Evaluation of Peppermint Leaf Flavonoids as SARS-CoV-2 Spike Receptor-Binding Domain Attachment Inhibitors to the Human ACE2 Receptor: A Molecular Docking Study
NNoname manuscript No. (will be inserted by the editor)
Evaluation of Peppermint Leaf Flavonoids as SARS-CoV-2Spike Receptor-Binding Domain Attachment Inhibitors tothe Human ACE2 Receptor: A Molecular Docking Study
Marcelo Lopes Pereira J´unior † , ∗ and Luiz Antˆonio Ribeiro J´unior † , ‡ Received: xx/xx/2021 / Accepted: xx/xx/2021
Abstract
One of the strategies in combating COVID-19 consists of virtual screening for possible inhibitors forthe attachment of SARS-CoV-2 Spike receptor-bindingdomain (RBD) to the human ACE2 receptor. Here, weperformed a molecular docking study to propose po-tential candidates to prevent the RBD/ACE2 attach-ment. These candidates are sixteen different flavonoidspresent in the peppermint leaf. Results showed that Lu-teolin 7-O-neohesperidoside is the peppermint flavonoidwith a higher binding affinity regarding the RBD/ACE2complex (about -9.18 Kcal/mol). On the other hand,Sakuranetin was the one with the lowest affinity (about-6.38 Kcal/mol). Binding affinities of the other pep-permint flavonoids ranged from -6.44 Kcal/mol up to-9.05 Kcal/mol. The biding site surface analysis showedpocket-like regions on the RBD/ACE2 complex thatyield several interactions (mostly hydrogen bonds) be-tween the flavonoid and the amino acid residues of theproteins. This study can open channels for the under-standing of the roles of flavonoids against COVID-19infection.
Keywords
Coronavirus, SARS-CoV-2, Peppermint Flavonoids,RBD/ACE2 Inhibitors.
The COVID-19 is an infectious disease caused by thecoronavirus SARS-CoV-2 [1–5]. It has reached the sta- † Institute of Physics, University of Bras´ılia, P.O. Box 04531,70.919-970, Bras´ılia, DF, Brazil. ‡ PPGCIMA, Campus Planaltina, University of Bras´ılia,73345-010, Bras´ılia, Brazil. ∗ Corresponding Author: [email protected] tus of a pandemic in March of 2020. Up to January of2021, it has already infected more than 100 million peo-ple, leading to the death of more than 2 million ones[6]. Since the earlier stages of this pandemic, a world-wide effort has been devoted to producing vaccines andantiviral drugs to combat this virus. Some successfulinvestigations yielded vaccines that have started to beapplied very recently [7–15]. Despite the beginning ofvaccination, no consensus about an efficient treatmentfor already infected patients has been reached so far.Sars-CoV-2 has a crown-like (spherical) form, andits surface protein (Spike) is directly involved in theinfectious process [16–18]. The receptor of this virusin human cells is the angiotensin-converting enzyme2 (ACE2) [19–21]. Sars-CoV-2 surface protein has twosubdivisions named S1 and S2, being S1 the receptor-binding domain (RBD) [22–25]. The RBD plays a ma-jor role in the attachment mechanism of Spike proteinto ACE2 [26]. After the attachment between them, thevirus enters the cell and starts the replication process[22]. In this sense, the strategy of virtual screening forpossible inhibitors for the RBD/ACE2 attachment [27]may pave the way for novel therapeutic approaches forthe treatment of COVID-19.Drug repurposing is a feasible way to combat dis-eases with some similarities [28–30]. In this scenario,the use of phytochemicals is always an important op-tion to be considered [31]. Among their sub-classes, theflavonoids — a class of small molecules found in fruits,vegetables, flowers, honey, teas, and wines — stand out[32–34]. Their pharmacological properties include an-timicrobial, antioxidant, anti-inflammatory, and antivi-ral functions [35–37].Flavonoids have been employed as inhibitors for theinfection mechanism of several diseases [39]. Amongthem, one can mention malaria, leishmaniasis, Chagas, a r X i v : . [ q - b i o . B M ] F e b Marcelo Lopes Pereira J´unior † , ∗ and Luiz Antˆonio Ribeiro J´unior † , ‡ ACE2RBD SARS-CoV-2
Fig. 1
Schematic representation of the (a) main proteins involved RBD/ACE2 interaction. These proteins were obtained fromProtein Data Bank, ID 6M0J [38]. (b) The binding site surface has the following color scheme: gray, red, blue, and white forcarbon, oxygen, nitrogen, and hydrogen atoms, respectively. and dengue [40–45]. They have also been consideredin studies aimed at developing therapeutic approachesfor cancer treatment [46–48]. Very recently, it was re-ported that Luteolin (a flavonoid found in leaves andshells) is efficient as an anti-inflammatory that can in-teract with the Sars-CoV-2 surface [49, 50]. More specif-ically, it is adsorbed in the Spike protein, inhibiting theSars-CoV-2 attachment to the ACE2, thus preventinginfection. Ngwa and colleagues used computer simula-tions to address the feasibility of Caflanone, Hesperetin,and Myricetin flavonoids in acting as inhibitors for theRBD/ACE2 attachment [51]. Their results pointed tothe ability of Caflanone in inhibiting the transmissionof the Sars-CoV-2 virus from mother to fetus in preg-nancy. Pandey et. al. conducted molecular docking anddynamics simulations considering ten flavonoid and non-flavonoid compounds (by using phytochemicals and hy-droxychloroquine, respectively) to verify their perfor-mance in inhibiting the RBD/ACE2 interaction [52].Their findings indicate that Fisetin, Quercetin, and Kam-ferol molecules couple to RBD/ACE2 complex with goodbinding affinities. In this sense, they can be exploredas possible anti-Sars-CoV-2 agents. Despite the successof these molecules inhibiting the RBD/ACE2, otherflavonoids should be tested to broaden the list of pos-sible inhibitors and to confirm their potential in devel-oping new therapeutic approaches for the treatment ofCOVID-19.Herein, in silico molecular docking analysis was car-ried out to propose potential flavonoid candidates inpreventing the RBD/ACE2 attachment. These candi- dates are sixteen different flavonoids present in the Pep-permint (Mentha piperita) leaf [53–59]. Peppermint isa perennial herb and medicinal plant native to Eu-rope widely used for treating stomach pains, headaches,and inflammation of muscles [54, 58, 59]. Well-known fortheir flavoring and fragrance traits, peppermint leavesand the essential oil extracted from them are used infood, cosmetic and pharmaceutical products [53–56].Our results revealed that Luteolin 7-O-neohesperidosideis the peppermint flavonoid with a higher binding affin-ity regarding the RBD/ACE2 complex (-9.18 Kcal/mol).On the other hand, Sakuranetin was the one with thelowest affinity (about -6.38 Kcal/mol). Binding affini-ties of the other peppermint flavonoids ranged from-6.44 Kcal/mol up to -9.05 Kcal/mol. These bindingaffinities are equivalent to other ones reported in theliterature for the interaction between flavonoids and theRBD/ACE2 complex [49, 50, 60–67]. Moreover, the bid-ing site surface analysis showed pocket-like regions onthe RBD/ACE2 complex that yield several interactions(mostly hydrogen bonds) between the flavonoid and theamino acid residues of the proteins. Definitively, exper-imental studies and clinical trials should be further per-formed to evaluate the efficacy of these compounds inthe inhibition of the RBD/ACE2 attachment.
Since Sars-CoV-2 infects human cells through the RBD-ACE2 coupling, the idea of checking for small moleculesthat may inhibit this interaction is recurring and can be itle Suppressed Due to Excessive Length 3
O O OHOHO (a) Acacetin
O OHOOHOH (b) Apigenin
OHOHOO OHOHOHOOOHOOOH (c) Apigenin*
O OHOOHOH O (d) Chryseoriol
OHOHOHOOOHOHOH OOOHOOOHO (e) Hesperidin
O OH O OHOHO (f) Hesperitin
O O OH OHOO (g) Ladanein
O OHOHOOHOH (h) Luteolin
O OHOHOOHOOHOHOH OOH (i) Luteolin*
O OHOHOOHOOHOHOH OOHO (j) Luteolin**
OHOHOHOO OHOHOHOOOHOOOHOH (k) Luteolin***
OOHOH O OH (l) Narigenin
OO O OH OHOOO (m) Pebrellin
OOH O O OH (n) Sakuranetin
OOH OH OOO OH (o) Thymusin
OOOOHOOOH (p) Xanthomicrol
Fig. 2
Chemical structure of peppermint leaf flavonoids: (a )Acacetin, (b) Apigenin, (c) Apigenin 7-O-neohesperidoside (Api-genin*), (d) Chryseoriol, (e) Hesperidin, (f) Hesperitin, (g) Ladanein, (h) Luteolin, (i) Luteolin 7-O-glucoside (Luteolin*),(j) Luteolin 7-O-glucuronide (Luteolin**), (k) Luteolin 7-O-neohesperidoside (Luteolin***), (l) Narigenin, (m) Pebrellin, (n)Sakuranetin, (o) Thymusin, and (p) Xanthomicrol. useful to propose a combatant drug [68]. Here, we usedmolecular docking to study the interaction between thepeppermint flavonoids with the RBD/ACE2 complex.Below, we present the proteins, inhibitors (flavonoids),and the computational protocol involved in our study.2.1 Protein PreparationFigure 1 presents the main proteins involved RBD/ACE2 interaction that were obtained from Protein DataBank, ID 6M0J [38]. In the left panel of this figure,the ACE2 protein is in blue, while the RBD Sars-CoV-2 one in red. Three essential regions of inhibition be-tween these proteins were highlighted with the blacksquares 1, 2, and 3. In the right side of Figure 1 weshow the binding site surface colored as gray, red, blue,and white for carbon, oxygen, nitrogen, and hydrogenatoms, respectively. The yellow rectangle highlights thetotal surface for inhibition with a clear cavity withinregion 2. 2.2 Ligand PreparationThe peppermint leaf contains sixteen flavonoids [53, 56],classified into three subcategories: Flavones (Flavonols),Flavorings, and Flavanones [53, 56]. The flavonoids stud-ied here are Acacetin, Apigenin, Apigenin 7-O-neohespe-ridoside (Apigenin*), Chryseoriol, Hesperidin, Hesper-itin, Ladanein, Luteolin, Luteolin 7-O-glucoside (Lute-olin*), Luteolin 7-O-glucuronide (Luteolin**), Luteolin7-O-neohesperidoside (Luteolin***), Narigenin, Pebrel-lin, Sakuranetin, Thymusin, and Xanthomicrol. Their3D structures were extracted from PubChem [69]. Thechemical structures of these flavonoids can be seen infigure 2, while relevant information such as PubChemID, molecular weight, molecular formula, and subcate-gory of the flavonoid is presented in table 1.
Marcelo Lopes Pereira J´unior † , ∗ and Luiz Antˆonio Ribeiro J´unior † , ‡ Compound PubChem CID Mol. Weight (g/mol) Mol. Formula Type
Acacetin 5280442 284.26 C H O Flavones and FlavonolsApigenin 5280443 270.24 C H O Flavones and FlavonolsApigenin* 5282150 578.5 C H O Flavones and FlavonolsChryseoriol 5280666 300.26 C H O Flavones and FlavonolsHesperidin 10621 610.6 C H O FlavoringsHesperitin 72281 302.28 C H O FlavanonesLadanein 3084066 314.29 C H O Flavones and FlavonolsLuteolin 5280445 286.24 C H O Flavones and FlavonolsLuteolin* 5280637 448.4 C H O Flavones and FlavonolsLuteolin** 5280601 462.4 C H O Flavones and FlavonolsLuteolin*** 5282152 594.5 C H O Flavones and FlavonolsNaringenin 932 272.25 C H O FlavoringsPebrellin 632255 374.3 C H O Flavones and FlavonolsSakuranetin 73571 286.28 C H O FlavanonesThymusin 628895 330.29 C H O Flavones and FlavonolsXanthomicrol 73207 344.3 C H O Flavones and Flavonols
Table 1
Potential inhibitors (peppermint leaf flavonoids) of RBD/ACE2 complex and their compound information.
After successful docking of the peppermint flavonoids tothe RBD/ACE2 complex, several modes of ligand/targetinteractions were generated with a particular dockingscore (binding affinity). The biding mode with the leastbiding energy is regarded as the best one, once it tendsto be the most stable. The binding affinity results ( ∆G )obtained here are summarized in Table 2. SWISSDOCKsimulations for all the ligands in Figure 2 revealed sig-nificant biding affinities with the target RBD/ACE2proteins. Luteolin 7-O-neohesperidoside is the pepper- Compound ∆G [Kcal/mol] Acacetin -6.70Apigenin -6.87Apigenin 7-O-neohesperidoside -8.08Chryseoriol -6.78Hesperidin -8.67Hesperitin -6.80Ladanein -6.56Luteolin -7.24Luteolin 7-O-glucoside -8.01Luteolin 7-O-glucuronide -7.74Luteolin 7-O-neohesperidoside -9.18Naringenin -6.44Pebrellin -7.07Sakuranetin -6.38Thymusin -6.94Xanthomicrol -6.83
Table 2
Peppermint leaf-based flavonoid candidates under-going docking experiment with their best docking score (low-est binding affinity ∆G in Kcal/mol). mint flavonoid with a higher binding affinity regard-ing the RBD/ACE2 complex (about -9.18 Kcal/mol).On the other hand, Sakuranetin was the one with thelowest affinity (approximately -6.38 Kcal/mol). Bind-ing affinities of the other peppermint flavonoids rangedfrom -6.44 Kcal/mol up to -9.05 Kcal/mol. As one cannote in Tables 1 and 2, the best docked flavonoids havegreater molecular weight. All the binding affinities areclose to the ones reported for the RBD/ACE2 inter-action with other species of flavonoids [49, 50, 60–67].Moreover, they can outperform the binding affinitiesreported by docking studies using other types of com-pounds targeting RBD/ACE2 [63, 75–81], such as Chloro-quine and Hydroxychloroquine, which are lower than-8.0 Kcal/mol [63]. This fact can be attributed to theabundant phenolic hydroxyl group in flavonoids. Thehydroxyl group in the sugar group of flavonoids tends itle Suppressed Due to Excessive Length 5 (a) Acacetin (b) Apigenin(c) Apigenin* (d) Chryseoriol(e) Hesperidin (f) Hesperetin(g) Ladanein (h) Luteolin Fig. 3
Biding site surface (BSS) for the putative best docking target/ligand configurations of (a) Acacetin, (b) Apigenin, (c)Apigenin ∗ , (d) Chryseoriol, (e) Hesperidin, (f) Hesperetin, (d) Ladanein, and (d) Luteolin. to bind more easily with the heteroatoms of amino acidsfrom RBD/ACE2, as will be shown later. In this sense,the peppermint flavonoids can compose the list of po-tential phytochemical inhibitors for the RBD/ACE2 in-teraction.Figures 3 and 4 illustrate the biding site surface(BSS) for the putative best docking target/ligand con-figurations. For the sake of clarity, these figures showthe BSS only for the RBD/ACE2 region highlightedby the yellow rectangle in Figure 1(b). The followingcolor scheme is adopted for the BSSs: gray, red, blue,and white for carbon, oxygen, nitrogen, and hydro-gen atoms, respectively. In the ball-stick representationfor the flavonoids, the carbon, oxygen, and hydrogen atoms are shown in the colors cyan, red, and white, re-spectively. As a general trend, one can note that theflavonoids fit inside the core pocket region (cavity) ofthe RBD/ACE2 complex. This cavity is displayed as re-gion 2 in Figure 1(a). Acacetin, Luteolin ∗ , Luteolin ∗∗ ,Thymusin, and Xanthomicrol were adsorbed on region1 (see Figure 1(a)) of the RBD/ACE2 complex. The lig-ands tend to interact with the oxygen atoms (red spotsin the BSS) in regions 1 and 2. These regions establishpocket-like media that yield interactions (mostly hydro-gen bonds) between flavonoids and amino acid residuesof proteins.Figures 5 and 6 provide a clear picture of the inter-action between the amino acid residues of the proteins Marcelo Lopes Pereira J´unior † , ∗ and Luiz Antˆonio Ribeiro J´unior † , ‡ (a) Luteolin* (b) Luteolin**(c) Luteolin*** (d) Naringenin(e) Pebrellin (f) Sakuranetin(g) Thymusin (h) Xanthomicrol Fig. 4
Biding site surface (BSS) for the putative best docking target/ligand configurations of (a) Luteloin ∗ , (b) Luteloin ∗∗ ,(c) Luteloin ∗∗∗ , (d) Naringenin, (e) Pebrellin, (f) Sakuranetin, (d) Thymusin, and (d) Xanthomicrol. and peppermint flavonoids. The docked poses (obtainedusing PLIP [74] show the residues names and the bondtypes. In the stick representation of flavonoids, the car-bon and oxygen atoms are in the orange and red col-ors, respectively. The hydrogen, hydrophobic, and π -staking bonds are denoted by the blue, dashed gray,and dashed yellow lines, respectively. The yellow sphererepresents the charge center. In Figure 5 one can notethat Acacetin, Apigenin, Apigenin ∗ , Chryseoriol, Hes-peridin, Hesperetin, Ladenein, and Luteolin interact withRBD/ACE2 mainly through 4, 5, 5, 6, 12, 5, 4, and 8 hy-drogen bonds with distinct amino acid residues in bothRBD and ACE2 proteins. Similarly, Figure 6 shows theinteraction mechanism between Luteloin ∗ , Luteloin ∗∗ , Luteloin ∗∗∗ , Naringenin, Pebrellin, Sakuranetin, Thy-musin, and Xanthomicrol with RBD/ACE2 is mediatedby 7, 5, 9, 8, 5, 5, 4, and 4 hydrogen bonds with dis-tinct amino acid residues in both RBD and ACE2 pro-teins, respectively. In total, 12 hydrophobic bonds werefound. The flavonoids and amino acid residues of theproteins involved in this kind of interaction are high-lighted below. Some π -stacking bonds are also presentin the RBD/ACE2 interactions with flavonoids expect-ing for the Hesperidin (Figure 5(e)), Luteolin ∗ (Figure6(a)), and Xanthomicrol (Figure 6(h)) cases.Generally speaking, we identified 31 distinct aminoacid residues of the RBD/ACE2 interacting with thepeppermint flavonoids. The RBD amino acid residues itle Suppressed Due to Excessive Length 7 TYR738GLU5SER1 ASP12 LYS682 (a) Acacetin
GLU671GLN674LYS682ASN15PHE372 GLU19ARG375 (b) Apigenin
PRO371ASN15 TYR770ASP670ARG668GLU671GLN674 (c) Apigenin*
LYS682 GLN674 GLU671 ARG375GLU19PHE372 (d) Chryseoriol
LYS682GLN674 GLU671ASP670ARG668 TYR770ARG375PHE372ASN15ASP12THR74ASN72 (e) Hesperidin
ARG668 TYR770GLU19ASN15 ARG375ALA369 (f) Hesperetin
GLY761GLU19ARG668ALA369 ARG37 (g) Ladanein
ARG668GLU671GLN674LYS682 TYR770GLU19ARG375PHE372ASN15 (h) Luteolin
Fig. 5
PLIP docked poses for the RBD/ACE2 interaction with (a) Acacetin, (b) Apigenin, (c) Apigenin ∗ , (d) Chryseoriol, (e)Hesperidin, (f) Hesperetin, (d) Ladanein, and (d) Luteolin. The hydrogen, hydrophobic, and π -staking bonds are denoted bythe blue, dashed gray, and dashed yellow lines, respectively. The yellow sphere represents the charge center. (and their occurrence) are TYR738 (4), LYS682 (5),GLU761 (6), GLN674 (6), TYR770 (6), ARG688 (8),ASP670 (2), GLY761 (4), GLY741 (2), GLN39 (1), ALA740 (1), LYS723 (3), ARG673 (1), and SER759 (1). TheACE2 amino acid residues (and their occurrence) areGLU5 (3), SER1 (5), ASP12 (7), PHE372 (4), ARG375 (9), ASN15 (8), GLU19 (9), PRO371 (1), ANS15 (1),THR71 (1), ALA369 (4), ARG37 (1), ALA368 (1), LYS335 (2), ASP20 (1), TYR760 (1), and LYS8 (1). Thisresult suggests that the target RBD/ACE2 amino acidresidues for this class of phytochemicals are ARG375,ASN15, and GLU19 from ACE2, and ARG668 from Marcelo Lopes Pereira J´unior † , ∗ and Luiz Antˆonio Ribeiro J´unior † , ‡ ASP12LYS723GLN739GLY741 GLU5SER1 (a) Luteolin*
LYS723 TYR738 ASP12SER1GLY741 ALA740GLU5 (b) Luteolin**
ASN15ASP12 ARG375 ALA368GLU671ARG668 ARG673GLN674 (c) Luteolin***
SER759 GLY761 LYS335TYR770ARG668GLU19ARG375ALA369ASN15 (d) Naringenin
ARG668ARG375GLU19ASN15 ASP20ALA369TYR760GLY761 (e) Pebrellin
GLY761LYS335GLU19TYR770ARG375ASN15ARG668 (f) Sakuranetin
SER1LYS723 TYR738LYS8 ASP12 (g) Thymusin
SER1 LYS723 TYR738 ASP12 (h) Xanthomicrol
Fig. 6
PLIP docked poses for the RBD/ACE2 interaction with (a) Luteloin ∗ , (b) Luteloin ∗∗ , (c) Luteloin ∗∗∗ , (d) Naringenin,(e) Pebrellin, (f) Sakuranetin, (d) Thymusin, and (d) Xanthomicrol. The hydrogen, hydrophobic, and π -staking bonds aredenoted by the blue, dashed gray, and dashed yellow lines, respectively. The yellow sphere represents the charge center. RBD, based on their higher occurrence. The flavonoidsthat present hydrophobic bonds with the RBD/ACE2amino acids, highlighted in the following as (flavonoid/residue), are Ladanein/GLU19, Luteolin/LYS682, Hes-peretin/ASN15, Hesperetin/GLU19, Pebrellin/TYR760,Sakuranetin/GLU19, Thymusin/LY58, Acacetin/GLU5, Apigenin/ASN15, Apigenin/PRO371, Apigenin/TYR770,and Chryseoriol/LYS682. itle Suppressed Due to Excessive Length 9
In summary, a set of phytochemicals (peppermint flavo-noids) were screened against the SARS-CoV-2 Spikereceptor-binding domain interacting with the humanACE2 receptor. The approach is based on computation-ally fitting small molecules for the target RBD/ACE2complex proteins using the 3D structure of the activesite with SWISSDOCK [70, 71], subsequently the rank-ing of the docked compounds with Quimera [73] andinteraction analysis with PLIP [74]. Results revealedthat Luteolin 7-O-neohesperidoside is the peppermintflavonoid with a higher binding affinity regarding theRBD/ACE2 complex (about -9.18 Kcal/mol). On theother hand, Sakuranetin was the one with the low-est affinity (about -6.38 Kcal/mol). Binding affinitiesof the other peppermint flavonoids ranged from -6.44Kcal/mol up to -9.05 Kcal/mol. These values outper-form the binding affinities reported by docking studiesusing other types of compounds in which the RBD/ACE2 complex was also the target. The biding site sur-face analysis showed pocket-like regions on the RBD/ACE2 complex that yield several interactions (mostlyhydrogen bonds) between the flavonoid and the aminoacid residues of the proteins. The interaction mecha-nism between the flavonoids and amino acid residues ofthe proteins is mediated by hydrogen bonds, essentially.The presence of some hydrophobic and π − stacking bonds was also observed. In total, we identified 31 dis-tinct amino acid residues of the RBD/ACE2 interactingwith the peppermint flavonoids. The target RBD/ACE2amino acid residues for this class of phytochemicals areARG375, ASN15, and GLU19 from ACE2, and ARG668from RBD, based on their higher occurrence. Acknowledgements
The authors gratefully acknowledge the financial sup-port from Brazilian Research Councils CNPq, CAPES,and FAPDF and CENAPAD-SP for providing the com-putational facilities. M.L.P.J. gratefully acknowledge thefinancial support from CAPES grant 88882.383674/2019-01. L.A.R.J. gratefully acknowledges respectively, thefinancial support from FAP-DF grant 00193.0000248/2019-32, CNPq grant 302236/2018-0, and UnB/DPI/DEXEdital 01/2020 grant 23106.057604/2020-05. The molec-ular graphics and analyses were performed with UCSFChimera, developed by the Resource for Biocomput-ing, Visualization, and Informatics at the University ofCalifornia, San Francisco, with support from NIH P41-GM103311.
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