Allosteric Modulation of Small Molecule Drugs on ACE2 Conformational Change upon Binding to SARS-CoV-2 Spike Protein

Wang, Duen-Shian; Hayatshahi, Hamed S.; Jayasinghe‐Arachchige, Vindi M.; Liu, Jin

doi:10.1109/bibm52615.2021.9669438

Cited by 5 publications

(6 citation statements)

References 64 publications

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“…The sites of interaction between ACE2 and SARS-CoV-2 represent important pharmacological targets to synthesize compounds directed against this site of action. In addition, vitamin D administration raises ACE2 levels [ 42 ], potentially representing a role in combating severe complications from COVID-19. In addition, viral delivery systems using adenoviruses, adeno-associated viruses, or lentiviruses have been used as approaches to increase ACE2 expression in vivo in the central nervous system and a variety of peripheral tissues.…”

Section: Pharmacological Approach On Ace2mentioning

confidence: 99%

Pharmacotherapy Based on ACE2 Targeting and COVID-19 Infection

Vitiello¹,

Ferrara²

2022

IJMS

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The new SARS-CoV-2 coronavirus is responsible for the COVID-19 pandemic. A massive vaccination campaign, which is still ongoing, has averted most serious consequences worldwide; however, lines of research are continuing to identify the best drug therapies to treat COVID-19 infection. SARS-CoV-2 penetrates the cells of the host organism through ACE2. The ACE2 protein plays a key role in the renin–angiotensin system (RAS) and undergoes changes in expression during different stages of COVID-19 infection. It appears that an unregulated RAS is responsible for the severe lung damage that occurs in some cases of COVID-19. Pharmacologically modifying the expression of ACE2 could be an interesting line of research to follow in order to avoid the severe complications of COVID-19.

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Section: Pharmacological Approach On Ace2mentioning

confidence: 99%

Pharmacotherapy Based on ACE2 Targeting and COVID-19 Infection

Vitiello¹,

Ferrara²

2022

IJMS

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“…Recent work by Wang et al also indicates that an allosteric site of ACE-2 is located in close proximity to the active site. 17 The surrounding amino acid residues of the AS1 are F428, P289, R288, N290, E430, L418, P415, I291, T434, E435, N437, K541, T414, M366, F438, L439, K441, Y279, A413, H540, C542, A412, L539, Y587, Q442, L410, L370, and Q526 with a cavity volume of 448.4 Å 3 ( Table 1 ). Furthermore, according to the AlloFinder algorithm, AS1 has an AlloScore of 8.18, suggesting it could be druggable.…”

mentioning

confidence: 99%

“…A recent study by Wang et al showed that dexamethasone (DEX), chloroquine (CQ), and telmisartan (TLS) disrupt the interactions between the SARS-CoV-2 spike protein and human ACE-2 through binding to an allosteric site by a conformational shift of the ACE-2. 17 And modulating the conformation of ACE2 may limit SARS-CoV-2 invasion owing to unfavored poses for spike protein binding. 17 However, the binding of a drug at an allosteric site of ACE-2 may also reduce the enzymatic substrate conversion of angiotensin-I and -II.…”

mentioning

confidence: 99%

“… 17 And modulating the conformation of ACE2 may limit SARS-CoV-2 invasion owing to unfavored poses for spike protein binding. 17 However, the binding of a drug at an allosteric site of ACE-2 may also reduce the enzymatic substrate conversion of angiotensin-I and -II. In addition, an allosteric drug for the ACE-2 receptor may probably be beneficial to reduce the stress on the renin-angiotensin system and to inhibit SARS-CoV-2 induced impaired endothelial function.…”

mentioning

confidence: 99%

“…Allosteric site-2 (AS2) and -3 (AS3) are found in close proximity to the interacting amino acid residues, that are usually participating in hydrogen bonding with the receptor-binding domain (RBD) of SARS-CoV-2 (Figure ). Recent work by Wang et al also indicates that an allosteric site of ACE-2 is located in close proximity to the active site . The surrounding amino acid residues of the AS1 are F428, P289, R288, N290, E430, L418, P415, I291, T434, E435, N437, K541, T414, M366, F438, L439, K441, Y279, A413, H540, C542, A412, L539, Y587, Q442, L410, L370, and Q526 with a cavity volume of 448.4 Å 3 (Table ).…”

mentioning

confidence: 99%

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Allosteric Site of ACE-2 as a Drug Target for COVID-19

Dutta

2022

ACS Pharmacol. Transl. Sci.

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The coronavirus disease 2019 (COVID-19) pandemic has a significant impact on healthcare systems and our lives. Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provide protection against SARS-CoV-2. However, mutations in the viral genome are common, raising concerns about the effectiveness of existing vaccines for SARS-CoV-2. The receptor-binding domain (RBD) of SARS-CoV-2 uses angiotensin-converting enzyme-2 (ACE-2) as a gateway to enter host cells. Therefore, the ACE-2-RBD interaction may be targeted by antiviral drugs. In this context, allosteric modulation of ACE-2 may offer a promising approach. It may lead to allosteric inhibition of the interaction between ACE-2 and SARS-CoV-2.

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Butein as a potential binder of human ACE2 receptor for interfering with SARS-CoV-2 entry: a computer-aided analysis

et al. 2022

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Natural products have been included in our dietary supplements and have been shown to have numerous therapeutic properties. With the looming danger of many zoonotic agents and novel emerging pathogens mainly of viral origin, many researchers are launching various clinical trials, testing these compounds for their antiviral activity. The present work deals with some of the available natural compounds from the literature that have demonstrated activity in counteracting pathogen infections. Accordingly, we screened, using in silico methods, this subset of natural compounds for searching potential drug candidates able to interfere in the recognition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and its target human angiotensin-converting enzyme 2 ( h ACE2) receptor, leading to the viral entry. Disrupting that recognition is crucial for slowing down the entrance of viral particles into host cells. The selected group of natural products was examined, and their interaction profiles against the host cell target protein ACE2 were studied at the atomic level. Based on different computer-based procedures including molecular docking, physicochemical property evaluation, and molecular dynamics, butein was identified as a potential hit molecule able to bind the h ACE2 receptor. The results indicate that herbal compounds can be effective for providing possible therapeutics for treating and managing coronavirus disease 2019 (COVID-19) infection. Graphical abstract

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Allosteric Modulation of Small Molecule Drugs on ACE2 Conformational Change upon Binding to SARS-CoV-2 Spike Protein

Cited by 5 publications

References 64 publications

Pharmacotherapy Based on ACE2 Targeting and COVID-19 Infection

Pharmacotherapy Based on ACE2 Targeting and COVID-19 Infection

Allosteric Site of ACE-2 as a Drug Target for COVID-19

Butein as a potential binder of human ACE2 receptor for interfering with SARS-CoV-2 entry: a computer-aided analysis

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