In silico study the inhibition of angiotensin converting enzyme 2 receptor of COVID-19 by Ammoides verticillata components harvested from Western Algeria.
ABSTRACT: The objective of this present study is to focus on the in silico study to screen for an alternative drug that can block the activity of the angiotensin converting enzyme 2 (ACE2) as a receptor for SARS-CoV-2, potential therapeutic target of the COVID-19 virus using natural compounds (Isothymol, Thymol, Limonene, P-cymene and ?-terpinene) derived from the essential oil of the antiviral and antimicrobial plant Ammoides verticillata (Desf.) Briq. which is located in the occidental Algeria areas. This study reveals that Isothymol, a major component of this plant, gives the best docking scores, compared to, the co-crystallized inhibitor ?-D-mannose of the enzyme ACE2, to Captropil drug as good ACE2 inhibitor and to Chloroquine antiviral drug also involved in other mechanisms as inhibition of ACE2 cellular receptor. In silico (ADME), drug-likeness, PASS & P450 site of metabolism prediction, pharmacophore Mapper showed that the compound Isothymol has given a good tests results compared to the ?-D-mannose co-crystallized inhibitor, to Captopril and Chloroquine drugs. Also the other natural compounds gave good results. The Molecular Dynamics Simulation study showed good result for the Isotymol- ACE2 docked complex. This study revealed for the first time that Isothymol is a functional inhibitor of angiotensin converting enzyme 2 activity and the components of essential oils Ammoides verticillata can be used as potential inhibitors to the ACE2 receptor of SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
Project description:The recent new contagion coronavirus 2019 (COVID-19) disease is a new generation of severe acute respiratory syndrome coronavirus-2 SARS-CoV-2 which infected millions confirmed cases and hundreds of thousands death cases around the world so far. Molecular docking combined with molecular dynamics is one of the most important tools of drug discovery and drug design, which it used to examine the type of binding between the ligand and its protein enzyme. Global reactivity has important properties, which enable chemists to understand the chemical reactivity and kinetic stability of compounds. In this study, molecular docking and reactivity were applied for eighteen drugs, which are similar in structure to chloroquine and hydroxychloroquine, the potential inhibitors to angiotensin-converting enzyme (ACE2). Those drugs were selected from DrugBank. The reactivity, molecular docking and molecular dynamics were performed for two receptors ACE2 and [SARS-CoV-2/ACE2] complex receptor in two active sites to find a ligand, which may inhibit COVID-19. The results obtained from this study showed that Ramipril, Delapril and Lisinopril could bind with ACE2 receptor and [SARS-CoV-2/ACE2] complex better than chloroquine and hydroxychloroquine. This new understanding should help to improve predictions of the impact of such alternatives on COVID-19. Communicated by Ramaswamy H. Sarma.
Project description:Angiotensin converting enzyme 2 (ACE2) plays a key role in renin-angiotensin system regulation and amino acid homeostasis. Human ACE2 acts as the receptor for severe acute respiratory syndrome coronaviruses SARS-CoV and SARS-CoV-2. ACE2 is also widely expressed in epithelial cells of lungs, heart, kidney and pancreas. It is considered an important drug target for treating SARS-CoV-2, as well as pulmonary diseases, heart failure, hypertension, renal diseases and diabetes. Despite the critical importance, the mechanism of ligand binding to the human ACE2 receptor remains unknown. Here, we address this challenge through all-atom simulations using a novel ligand Gaussian accelerated molecular dynamics (LiGaMD) method. Microsecond LiGaMD simulations have successfully captured both binding and unbinding of the MLN-4760 inhibitor in the ACE2 receptor. In the ligand unbound state, the ACE2 receptor samples distinct Open, Partially Open and Closed conformations. Ligand binding biases the receptor conformational ensemble towards the Closed state. The LiGaMD simulations thus suggest a conformational selection mechanism for ligand recognition by the ACE2 receptor. Our simulation findings are expected to facilitate rational drug design of ACE2 against coronaviruses and other related human diseases.
Project description:Coronavirus disease-2019 (COVID-19) has emerged as a pandemic affecting millions of adults. Severe acute respiratory syndrome coronavirus-2019 (SARS-CoV-2), the causative virus of COVID-19, infects host cells through angiotensin converting enzyme 2 (ACE2). Pre-clinical models suggest that ACE2 upregulation confers protective effects in acute lung injury. Additionally, renin-angiotensin aldosterone system inhibitors reduce adverse atherosclerotic cardiovascular disease, heart failure and chronic kidney disease outcomes, but may increase ACE2 levels. We review current knowledge of the role of ACE2 in cardiovascular physiology and SARS-CoV-2 virology as well as clinical data to inform the management of patients with or at risk for COVID-19 who require renin-angiotensin-aldosterone system inhibitor therapy.
Project description:Coronavirus disease 2019 is a major threat to public health globally. Though its pathogenesis has not been fully elucidated, angiotensin-converting enzyme 2 (ACE2) has been recently identified as a receptor for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the cell. Here, we aimed to clarify the potential role of ACE2 in SARS-CoV-2-induced acute lung injury and its underlying mechanism. As a receptor for coronavirus, ACE2 mediates the entry of SARS-CoV-2 into cells in a similar way as for severe acute respiratory syndrome coronavirus (SARS-CoV). The high binding affinity of SARS-CoV-2 to ACE2 correlates with its efficient spread among humans. On the other hand, ACE2 negatively regulates the renin-angiotensin-aldosterone system (RAAS) primarily by converting angiotensin II to angiotensin 1-7, which exerts a beneficial effect on coronavirus-induced acute lung injury. Human recombinant ACE2 has been considered as a potential therapy for SARS-CoV-2 by blocking virus entry and redressing the imbalance of RAAS in SARS-CoV-2 infection. The level of ACE2 expression can be upregulated by treatment with an ACE inhibitor (ACEI) or angiotensin ? type 1 receptor blocker (ARB). To date, no evidence shows that ACEIs or ARBs increase the susceptibility and mortality of patients infected with SARS-CoV-2, and hence, it is not advisable to discontinue such drugs in patients with cardiovascular disease.
Project description:Hydrogen sulfide has been suggested to play an essential role in atherogenesis. There is a paucity of information about the association between H2S and angiotensin converting enzyme 2 (ACE2), a novel homolog of ACE. Therefore, the aim of the study was to explore the role of H2S in atherosclerosis with respect to ACE2 both in vitro and in vivo. Here, a murine model of acutely disturbed flow-induced atherosclerosis by left common carotid artery (LCA) partial ligation was utilized. We found that carotid partial ligation in high-fat fed apoE-/- mice significantly inhibited endogenous H2S synthesis in LCA. Application of NaHS, an H2S donor considerably attenuated the severity of atherosclerosis with upregulating carotid expression of ACE2, thus converting pro-atherosclerotic angiotensin II (Ang II) to anti-atherosclerotic angiotensin 1-7 (Ang-(1-7)). The anti-atherosclerotic effect of NaHS was dramatically abolished by treatment with MLN-4760, an ACE2 inhibitor. In contrast, blockage of H2S formation by DL-propargylglycine exacerbated the burden of atherosclerotic plaques accompanied by inhibiting carotid expression of ACE2. At the cellular level, NaHS dose-dependently promoted the expression of ACE2 and conversion from Ang II to Ang-(1-7) in unstimulated or LPS-stimulated endothelial cells, thus exerting anti-inflammatory properties. The anti-inflammatory effect of NaHS was abrogated by pretreatment with DX600, a selective ACE2 inhibitor. In conclusion, these data provide direct evidences that endogenous H2S insufficiency exists in acute flow disturbance-induced atherosclerosis and that application of H2S may protect against atherosclerosis via upregulating ACE2 expression in endothelial cells.
Project description:The mechanism for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires the binding of the virus to the angiotensin-converting enzyme 2 (ACE2) receptor, well-known for its role in counteracting ACE. ACE2 is involved in modulating blood pressure and establishing blood pressure homeostasis. Recently, a critical debatable question has arisen whether using antihypertensive medications will have a favorable impact on people infected with SARS-CoV-2 or a deleterious one, mainly because angiotensin-converting enzyme inhibitor (ACEI) and angiotensin-receptor blocker (ARB) therapy can modulate the expression of ACE2 protein. The concern is that the use of ACEIs and ARBs will increase the expression of ACE2 and increase patient susceptibility to viral host cell entry and propagation. On the other hand, several genetic association studies have examined the relationship between ACE2 genetic variants and the risk of developing hypertension in different ethnic populations. In this review, we discuss the ongoing arguments in the literature about ACE2's role in mortality rate among coronavirus disease 2019 (COVID-19) patients comorbid with hypertension and critically evaluate the current debate about the usage or discontinuation of ACEI/ARB antihypertensive drugs. Moreover, we explore the two opposing roles that ACE2 genetic variants might be playing in COVID-19 by reducing ACE2 receptor effectiveness and mitigating SARS-CoV-2 infectivity.
Project description:A new coronavirus called SARS-CoV-2 is rapidly spreading around the world. Over 16,558,289 infected cases with 656,093 deaths have been reported by July 29th, 2020, and it is urgent to identify effective antiviral treatment. In this study, potential antiviral drugs against SARS-CoV-2 were identified by drug repositioning through Virus-Drug Association (VDA) prediction. 96 VDAs between 11 types of viruses similar to SARS-CoV-2 and 78 small molecular drugs were extracted and a novel VDA identification model (VDA-RLSBN) was developed to find potential VDAs related to SARS-CoV-2. The model integrated the complete genome sequences of the viruses, the chemical structures of drugs, a regularized least squared classifier (RLS), a bipartite local model, and the neighbor association information. Compared with five state-of-the-art association prediction methods, VDA-RLSBN obtained the best AUC of 0.9085 and AUPR of 0.6630. Ribavirin was predicted to be the best small molecular drug, with a higher molecular binding energy of -6.39 kcal/mol with human angiotensin-converting enzyme 2 (ACE2), followed by remdesivir (-7.4 kcal/mol), mycophenolic acid (-5.35 kcal/mol), and chloroquine (-6.29 kcal/mol). Ribavirin, remdesivir, and chloroquine have been under clinical trials or supported by recent works. In addition, for the first time, our results suggested several antiviral drugs, such as FK506, with molecular binding energies of -11.06 and -10.1 kcal/mol with ACE2 and the spike protein, respectively, could be potentially used to prevent SARS-CoV-2 and remains to further validation. Drug repositioning through virus-drug association prediction can effectively find potential antiviral drugs against SARS-CoV-2.
Project description:Emerging evidence suggests that cardiac angiotensin-converting enzyme 2 (ACE2) may contribute to the regulation of heart function and hypertension-induced cardiac remodeling. We tested the hypothesis that inhibition of ACE2 in the hearts of (mRen2)27 hypertensive rats may accelerate progression of cardiac hypertrophy and fibrosis by preventing conversion of angiotensin II (Ang II) into the antifibrotic peptide, angiotensin-(1-7) (Ang-(1-7)).Fourteen male (mRen2)27 transgenic hypertensive rats (12 weeks old, 401 + or - 7 g) were administered either vehicle (0.9% saline) or the ACE2 inhibitor, MLN-4760 (30 mg/kg/day), subcutaneously via mini-osmotic pumps for 28 days.Although ACE2 inhibition had no effect on average 24-h blood pressures, left ventricular (LV) Ang II content increased 24% in rats chronically treated with the ACE2 inhibitor (P < 0.05). Chronic ACE2 inhibition had no effect on plasma Ang II or Ang-(1-7) levels. Increased cardiac Ang II levels were associated with significant increases in both LV anterior, posterior, and relative wall thicknesses, as well as interstitial collagen fraction area and cardiomyocyte hypertrophy in the transgenic animals chronically treated with the ACE2 inhibitor. Cardiac remodeling was not accompanied by any further alterations in LV function.These studies demonstrate that chronic inhibition of ACE2 causes an accumulation of cardiac Ang II, which exacerbates cardiac hypertrophy and fibrosis without having any further impact on blood pressure or cardiac function.
Project description:Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1-7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enters permissive cells via an ACE2-mediated mechanism. The present in silico study attempted to repurpose existing drugs for use as prospective viral-entry inhibitors targeting human ACE2. Initially, a clinically approved drug library of 7,173 ligands was screened against the receptor using molecular docking, followed by energy minimization and rescoring of docked ligands. Finally, potential binders were inspected to ensure molecules with different scaffolds were engaged in favorable contacts with both the metal cofactor and the critical residues lining the receptor's active site. The results of the calculations suggest that lividomycin, burixafor, quisinostat, fluprofylline, pemetrexed, spirofylline, edotecarin, and diniprofylline emerge as promising repositionable drug candidates for stabilizing the closed (substrate/inhibitor-bound) conformation of ACE2, thereby shifting the relative positions of the receptor's critical exterior residues recognized by SARS-CoV-2. This study is among the rare ones in the relevant scientific literature to search for potential ACE2 inhibitors. In practical terms, the drugs, unmodified as they are, may be introduced into the therapeutic armamentarium of the ongoing fight against COVID-19 now, or their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors in the near future.
Project description:Although clinical manifestations of the 2019 novel coronavirus disease pandemic (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), are mainly respiratory symptoms, patients can also develop severe cardiovascular damage. Therefore, understanding the damage caused by SARS-COV-2 to the cardiovascular system and the underlying mechanisms is fundamental. The cardiovascular damage may be related to the imbalance of the renin-angiotensin-system (RAS) as this virus binds the Angiotensin-Converting-Enzyme 2 (ACE2), expressed on the lung alveolar epithelial cells, to enter into cells. Virus internalization may cause a downregulation of ACE2 on host cell surface that could lead to a local increased level of angiotensin II (AII) and a reduced level of angiotensin 1-7 (A1-7). An imbalance between these angiotensins may be responsible for the lung and heart damage. Pharmacological strategies that interfere with the viral attachment to ACE2 (umifenovir and hydroxychloroquine/chloroquine) or that modulate the RAS (analogous of A1-7 and ACE2, losartan) are in clinical development for COVID-19. The use of RAS inhibitors has also become a matter of public concern as these drugs may increase the mRNA expression and levels of ACE2 and impact the virulence and transmission of SARS-COV-2. Data on the effect of RAS inhibitors on ACE2 mRNA expression are scarce. Scientific societies expressed their opinion on continuing the therapy with RAS inhibitors in patients with COVID-19 and underlying cardiovascular diseases. In conclusion, RAS may play a role in SARS-COV-2-induced cardiac and pulmonary damage. Further studies are needed to better understand the role of RAS in COVID-19 and to guide decision on the use of RAS inhibitors.