key: cord-0873492-r5fbidda
authors: Xu, Yuan; Al-Mualm, Mahmood; Mergia Terefe, Ermias; Ilyasovna Shamsutdinova, Maksuda; Jade Catalan Opulencia, Maria; Alsaikhan, Fahad; Turki Jalil, Abduladheem; Thaeer Hammid, Ali; Enayati, Ayesheh; Mirzaei, Hassan; Khori, Vahid; Jabbari, Ali; Salehi, Aref; Soltani, Alireza; Mohamed, Abdullah
title: Prediction of COVID-19 manipulation by selective ACE inhibitory compounds of Potentilla reptant root: In silico study and ADMET profile
date: 2022-04-27
journal: Arab J Chem
DOI: 10.1016/j.arabjc.2022.103942
sha: 7635b1dd713b74223bc7e4ddfacde38b7ab402ba
doc_id: 873492
cord_uid: r5fbidda

In the novel SARS-CoV-2 (COVID-19) as a global emergency event, the main reason of the cardiac injury from COVID-19 is angiotensin-converting enzyme 2 (ACE2) targeting in SARS-CoV-2 infection. The inhibition of ACE2 induces an increase in the angiotensin II (Ang II) and the angiotensin II receptor type 1 (AT1R) leading to impaired cardiac function or cardiac inflammatory responses. The ethyl acetate fraction of Potentilla reptans L. root can rescue heart dysfunction, oxidative stress, cardiac arrhythmias and apoptosis. Therefore, isolated components of P. reptans evaluated to identify natural anti-SARS-CoV-2 agents via molecular docking. In silico molecular docking study were carried out using the Auto Dock software on the isolated compounds of Potentilla reptans root. The protein targets of selective ACE and others obtained from Protein Data Bank (PDB). The best binding pose between amino acid residues involved in active site of the targets and compounds was discovered via molecular docking. Furthermore, ADMET properties of the compounds were evaluated. The triterpenoids of P. reptans showed more ACE inhibitory potential than catechin in both domains. They were selective on the nACE domain, especially compound 5. Also, the compound 5 & 6 had the highest binding affinity toward active site of nACE, cACE, AT1R, ACE2, and TNF-α receptors. Meanwhile, compound 3 showed more activity to inhibit TXA2. Drug likeness and ADMET analysis showed that the compounds passed the criteria of drug likeness and Lipinski rules. The current study depicted that P. reptans root showed cardioprotective effect in COVID-19 infection and manipulation of angiotensin II-induced side effects.

In the novel SARS-CoV-2 (COVID-19) as a global emergency event, the main reason of the cardiac injury from COVID-19 is angiotensin-converting enzyme 2 (ACE2) targeting in SARS-CoV-2 infection. The inhibition of ACE2 induces an increase in the angiotensin II (Ang II) and the angiotensin II receptor type 1 (AT1R) leading to impaired cardiac function or cardiac inflammatory responses. The ethyl acetate fraction of Potentilla reptans L. root can rescue heart dysfunction, oxidative stress, cardiac arrhythmias and apoptosis. Therefore, isolated components of P. reptans evaluated to identify natural anti-SARS-CoV-2 agents via molecular docking.

In silico molecular docking study were carried out using the Auto Dock software on the isolated compounds of Potentilla reptans root. The protein targets of selective ACE and others obtained from Protein Data Bank (PDB). The best binding pose between amino acid residues involved in active site of the targets and compounds was discovered via molecular docking.

Furthermore, ADMET properties of the compounds were evaluated.

The triterpenoids of P. reptans showed more ACE inhibitory potential than catechin in both domains. They were selective on the nACE domain, especially compound 5. Also, the compound 5 & 6 had the highest binding affinity toward active site of nACE, cACE, AT1R, ACE2, and TNF-α receptors. Meanwhile, compound 3 showed more activity to inhibit TXA2.

Drug likeness and ADMET analysis showed that the compounds passed the criteria of drug likeness and Lipinski rules. The current study depicted that P. reptans root showed cardioprotective effect in COVID-19 infection and manipulation of angiotensin II-induced side effects.

Keyword: COVID-19, Potentilla reptans, Angiotensin II, Molecular docking simulation, ADMET.

A novel coronavirus (SARS-CoV-2, COVID-19) has caused a great threat to the public healthcare systems and international concern in the world [1] [2] [3] [4] . This virus affected seriously endangers human health by causing susceptibility, disease severity, various mutations and high mortality [5, 6] . As of now, there is not exact conventional medications for the SARS-CoV-2 treatment [5] . It seems that there are several mechanisms involved in SARS-CoV-2 infection in different organs including lung, heart, kidney, and brain [2, 7] . The main target of SARS-CoV-2 propagates is the angiotensin-converting enzyme 2 (ACE2) receptor and reninangiotensin system (RAS) of host as a vehicle to entry human cells and viral replication [8] .

However, SARS-CoV-2 exhibits cardiac dysfunctions (owing to ACE2 abundant in cardiac tissue) including acute myocardial injury, hypokalemia, arrhythmia, myocarditis, and sudden cardiac death [8] [9] [10] [11] [12] . At that point, there is a specific attention to manage ACE2 expression or COVID-19 cardiac adverse and its associated targets such as cardiac inflammatory, Ang II induction, cardiac arrhythmia signaling and oxidative stress. Viral binding to ACE2 leads to ACE2 shedding and an accumulation of Ang II and the angiotensin II receptor type 1 (AT1R), thereby causing an incidence of vasoconstriction, fibrosis, arrhythmogenesis, hypertrophy, proliferation, oxidative stress, cardiac dysfunction and myocardium sensitization [8, 13, 14] . On the other hand, there is the relationship between elevated ACE2 and some cardiac comorbidities such as heart failure, secondary hypertension, coronary artery disease, and cardiomyopathies, which may increase COVID-19 susceptibility and severity [8] . Likewise, angiotensin-I converting enzyme (ACE) inhibitors such as captopril, enalapril, and lisinopril are used to management of COVID-19 [15] . Owing to the non-selectivity of applied ACE inhibitors, they cause some side effects via associated dysregulatory of bradykinin in the patients [16] .

The many previous studies have indicated medicinal plants and natural products exert beneficial effects in treatment of COVID-19 [17] [18] [19] , and also, they demonstrated the hopeful ACE inhibitory activity [16] . In this perspective, a growing body of evidence indicates that Potentilla reptans L. (Rosaceae) can rescue heart dysfunction, oxidative stress, cardiac arrhythmias and apoptosis through inhibiting ROS, glucocorticoid regulated kinase-1 (SGK1), glycogen synthase kinase 3β (GSK-3β), BAX and caspase3 regards to increasing Nrf2, SOD, CAT, NO, BCl-2 and improving cardiac hemodynamic function [20] [21] [22] [23] [24] [25] [26] [27] .

To the best our knowledge, P. reptans, as a natural cardioprotective agent may be a promising complementary candidate of COVID-19 for warrant therapeutic intention of ACE2 targeting-COVID-19-induced cardiac adverse. Therefore, we aimed to evaluate isolated components of P. reptans to identify natural anti-SARS-CoV-2 agents via molecular docking pointing the selective ACE inhibition and some properties including physicochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET).

In this study, the anti-SARS-CoV-2 potential and the plausible selective-ACE inhibition (cACE or nACE domains) potential of P. reptans root compounds ( Figure 1 The docking was performed on the target proteins, which were removed water molecules/nonpolar hydrogen atoms and added polar hydrogens/kollman charges [29] [30] [31] . Lamarckian genetic algorithm (GA) was used for local search method with a grid box of 60×60×60 and point spacing of 0.375 Å that was set for creating of autogrid module [32, 33] . 150 GA runs were accomplished for each docking. Maestro 11.0 Schrodinger suit and Discovery Studio Visualizer software was applied for visualization of 2D and 3D presentation.

The 3D structure of each phytochemical ( Figure 1 ) was retrieved from PubChem database in SDF format and then converted into PDB format using Open Babel software. Chem3D software was utilized for energy minimization of ligands. Captopril, an ACE inhibitor not selective inhibitor, was used as a control.

Efficacy and safety profile of the mentioned natural compounds including absorption, distribution, metabolism, excretion and toxicity (ADMET) and their pharmacokinetics were predicted using admetSAR database [34] and swissADME [35] . Furthermore, we investigated topological polar surface area (TPSA) as an important descriptor predicting oral bioavailability and absorption of the compounds. Also, the compound effects on permeability of blood-brain barrier (BBB), inhibition of cytochrome P450 (CYP3A4, CYP2C9 and CYP2D6), AMES toxicity and carcinogenicity were evaluated.

According to table 1, the triterpenoids of P. reptans showed more ACE inhibitory potential than catechin in both domains. Also, they were selective on the nACE domain based on their lower binding energies on 6F9V and 6EN5 targets, especially compound 5 had the lowest binding energy. Between assessed-PDB IDs of cACE domain, the triterpenoids revealed their lower binding energy in the binding pocket of 6F9U, mainly compound 6 (-10.2 kcal/mol), and also, it acted as more selective for cACE with lower binding energy for 6F9T and 2OC2 (as cACE domain complexes).

In addition, the results indicated that P. reptans root compounds are ACE inhibitor regards to the binding energy of ATR-inhibitor complexes 4YAY and 4ZUD, but compounds 5 and 6 showed suitable energy for ATR inhibition and acted as angiotensin receptor blocker (ARB).

In ACE2 inhibitory investigation, triterpenoids were effective in the binding pocket of 1R4L protein especially compounds 5 and 2 (Table 1 ). In general, compounds 5 and 6 were more active in the inhibition of ACE, ACE2 and AT1R with their hydroxyl groups and electron donor -OMe substitution, thereby a preparation condition of interaction with the target Zn 2+ ion.

In the present study, the compound 5 interacted with the 6F9V target in its active sites Cys330, Leu139, Phe490, Trp257, Phe435, Tyr498, Tyr501, Ala332, Tyr122 and Phe505 through hydrophobic interaction (Fig. 2A) . Its polar interaction represented with residues Thr144, Arg350, Asp255, Lys489, His491, Ser260, Glu262, Asp393, Asp354, Glu431, and Ser504.

Furthermore, hydroxyl and carbonyl groups of the compound 5 formed 11 hydrogen bonds with the amino acid residues Asp415, Asn277, His353, Cys352, Ala354, Thr372, Asp377 and Fig. 2A) . On the other hand, compound 5 interacted with the Zn 2+ ion as essential element to binding the 6F9V target. Figure 2B illustrated hydrophobic interactions between the amino acid residues of target (6EN5) and compound 5. In addition, the polar interactions with amino acid residues Asp140, Asp354, Arg350, Gln355, Glu389, Asp393, Ser504, Ser357, Thr358, His361, Lys432, His491, and Lys489 with compound 5 were indicated, that Thr358 interaction is important in nACE selectivity of compound 5 [16] . Furthermore, the compound 5 formed 8 hydrogen bonds with residues His331, Thr144, His491, Tyr498, Tyr501, Gln259, and Ser260 of 6EN5 target at 2.85, 2.96, 2.33, 1.89, 2.77, 2.23, 2.53 and 2.74 Å, respectively (Supplementary material Figure S1 ).

As illustrated in figure 2C -E, the compound 6 revealed selective cACE domain in the active site of targets (6F9U, 6F9T and 2OC2) through polar, hydrogen bond or hydrophobic interactions between important residues of targets with its hydroxyl, carbonyl and methoxyl groups (Supplementary material Figure S2, S3, S4) . Also, compound 6 and zinc atom of 6F9U interacted at 1.7 Å.

In the AT1R inhibitory analysis, compound 5 and 6 showed the lowest bonding energy in 4ZUD and 4YAY, respectively ( Fig.3A-B , Supplementary material Figure S5 , S6). In addition, the result of this study indicated the ACE2 inhibitory energy for compound 5 is -9.9 kcal/mol in the interaction with key amino acid residues of 1R4L and binding to Zn 2+ ion at a distance of 2.9 Å (Fig.3C, Table 1 , Supplementary material Figure S7 ).

As shown Table1, the compounds did not significantly inhibit COX-1. Compound 6 showed an inhibitory effect, more than other triterpenoids, on TNF-α (Fig. 4A , Supplementary material Figure S8 ). In TXA2 inhibition compound 3 exerted binding affinity with residues Trp209 and Arg295 through its hydroxyl groups at 2.72 and 2.06 Å, respectively (Fig. 4B , Supplementary material Figure S9 ).

Pharmacokinetic and toxicity properties of compounds were determined. The results of predicted ADMET properties of compounds and toxicity profiles presented in Table 2 .

To get an insight about the compliance of compounds with Lipinski's Rule of Five, the compounds screened for more analysis. Notably, most compounds passed Lipinski rule and did not show any violation of standardized Lipinski rule of five. Values of calculated solubility of compounds ranging from -3.08 to -3.89 indicating moderate solubility of compounds, and also calculated Log P indicated between 1.29 and 3.26. Moreover, molecular weight was more than 500 Dalton, number of hydrogen bond donors were more than 5, while number of Hacceptors of compound 5 and 6 exhibited violation of Lipinski rule and others obey Lipinski rule [36] [37] [38] [39] [40] .

Molar refractivity of all compounds were more than 130. According to data presented in table 2 and 3 pharmacokinetic parameters and ADMET profiles (absorption, distribution, metabolism, excretion, and toxicity) evaluated to predict the toxicity parameters of the compounds. However, all the compounds are following the criteria of drug likeness rules. All the compounds indicated good absorption and permeability demonstrating moderate absorption. Evaluation of two key ADMET descriptors like Human Intestinal Absorption (HIA) and blood brain barrier (BBB) exhibited appropriate profiles. Furthermore, the obtained results revealed that all of the compounds were non-inhibitors of CYP450 enzymes (3A4, 2D6, and 2C9) acting as an effective factor in drug metabolism [41] [42] [43] [44] [45] . Additionally, most compounds were non-carcinogenic, non-hepatotoxicity, and non-AMES toxicity.

The previous studies established cardioprotective effects of P. reptans compounds in docking and animal experimental studies due to glycogen synthase kinase 3β (GSK-3β) and glucocorticoid regulated kinase-1 (SGK1) protein kinase inhibition [20, 23] . Likewise, they demonstrated an ischemic preconditioning property via antioxidant activity, nitric oxide release, activating Nrf2 pathway, and decreasing apoptotic markers in an isolated rat heart ischemia/reperfusion model [22] . Consistent with these data, P. reptans compounds may be applied for cardioprotection in COVID-19 by beneficial cardioprotective effects.

In this study, the isolated triterpenoids of P. reptans root showed selective ACE inhibitory effect as well as inhibition of ACE2 and AT1R, especially compound 5 and 6, compared with catechin (Table 1 ). However, it may be explained by hydroxyl groups and electron donor substances in chemical structure of triterpenoids. In addition, the compound 5 and 6 had the highest binding affinity toward active site of nACE, cACE, AT1R, and ACE2 receptors, through -OMe element or hydroxyl groups. Also, their non-covalent (hydrogen bond and hydrophobic) interactions have a significant role in occupation of active site of the targets. Therefore, compound 5 and 6 can be considered as a potential selective ACE inhibitor by binding to the key amino acid residues in the active site of the targets.

To the best of our knowledge, the selective inhibition of ACE plays a pivotal role in controlling the RAS and kallikrein-kinin system (KKS), thereby normal hydrolyzing of the antiinflammatory peptide N-acetyl-SDKP and bradykinin by nACE and cACE, respectively. Therefore, selective cACE inhibitors diminish the production of angiotensin-II (AngII), ACE2 and plausible angioedema. On the other hand, selective nACE inhibitors attenuate inflammation and fibrosis of heart, renal and vascular through increasing N-acetyl-SDKP levels [16, 46] . However, selective ACE inhibitors prevent the activity of cACE or nACE domains.

It seems that AT1R and ACE2 inhibitory effects of P. reptans triterpenoids (as shown table 1) can explain their suppressing effects in inflammatory and cardiac fibrosis induced by COVID-19 infection and dysfunction in RAS. It has been reported that AngII induced angiotensin II type-2 receptor (AT2R) and NO production when AT1R blocked and leads to cardioprotection and anti-fibrosis via inhibiting of norepinephrine, MAPK and ERK1/2 along with inducing vasodilation by bradykinin/NO/cGMP cascades [47] [48] [49] [50] . In addition, the previous studies indicated that isolated ingredients of P. reptans inhibited cardiac apoptosis via NO release, inhibiting GSK-3β and activating RISK/SAFE pathways in reperfusion injury [23] . On the other hand, AT1R inhibition may upregulate ACE2 levels as important target of SARS-CoV-2 [15] , thereby the P. reptans compounds can exert a protective role against an increase in ACE2 by their affinity to occupation of ACE2 complex.

In the next step, the current study demonstrated that compounds of P. reptans inhibited TXA2

and TNF-α (Table 1 ) as adverse effects of infection with COVID-19, which can be in line with mentioned properties of compounds and explain by their antioxidant and anti-inflammatory or anti-apoptotic effects [22, 23] . Furthermore, the recent study reported that AngII acts similar to inflammatory cytokine and induces hypertrophy, fibrosis, arterial fibrillation and arrhythmia in the heart [51] . Likewise, it can activate numerous kinases such as SGK1 that plays a pivotal dual role in the pathogenesis of cardiac arrhythmia, inflammation and remodeling in response to progressive elevated AngII [52, 53] . Agreeing with this evidence, ethyl acetate fraction of P. reptans exerted inhibitory effects on SGK1 to reduce arrhythmia and cardiac apoptosis in ischemia/reperfusion injury [20, 23] .

However, AngII and AT1R could cause arterial/ventricular fibrillation, thus, by blocking ACE or AT1R it would be plausible that inhibition of SGK1 to reduce the prolongation of the action potential duration (APD), hypokalemia, and the proarrhythmic effects of AngII [54] . Therefore, Potentilla reptans compounds may be promising candidate as anti-arrhythmic agent for management of ACE2

targeting-COVID-19-induced arrhythmia due to their ACE or AT1R inhibitory properties. Table 3 . ADMET (absorption, distribution, metabolism, excretion and toxicity) profile of compounds. 

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This article financially supported by Golestan University of Medical Sciences, Gorgan, Iran (IR.GOUMS.REC.1400.107).

The authors declare that there is no conflict of interest. The authors alone are responsible for the content of the paper.

Hepatotoxicity; P-GI: P-glycoprotein inhibitor. Caco2: A model of the intestinal epithelial barrier; AMES: To assess the mutagenic potential of chemical compounds. Fig. 1 .

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: