In Silico Comparison of Separate or Combinatorial Effects of Potential Inhibitors of the SARS-CoV-2 Binding Site of ACE2

Abstract

Background: The COVID-19 is a pandemic viral infection with a high morbidity rate, leading to many worldwide deaths since the end of 2019. The RBD (Receptor Binding Domain) of SARS-CoV-2 through its spike utilizes several host molecules to enter host cells. One of the most important ones is the angiotensin-converting enzyme 2 (ACE2), an enzyme normally engaged in renin angiotensin pathway and is responsible for hypertension regulation. As different articles have analyzed separate compounds which can bind ACE2 as the potential virus entry blockers, and each one with a different molecular docking algorithm, in this study we compared all candidate compounds individually as well as their combinations using a unique validated software to introduce most promising ones.
 Methods: We collected and prepared a list of all available compounds which potentially can inhibit RBD binding site of the ACE2 from different studies and then reanalyzed and compared them using the Patchdock (ver. 1.3) as a suitable molecular docking algorithm for analysis of separate compounds or their combinations.
 Results: Saikosaponin A (e.g. in Bupleurum chinense), Baicalin (e.g. in several species in the genus Scutellaria), Glycyrrhizin (Glycyrrhiza glabra), MLN-4760 and Umifenovir better occupied ACE2 to inhibit viral RBD binding and are suggested as the top five inhibitors of the SARS-CoV-2 binding site of ACE2. Their combinatory effects were also inspiring concurrent ACE2 blockade.
 Conclusion: The results propose greatest compounds and their combinatory anti-SARS-CoV-2 effects in order to decrease the time and expenses required for further experimental designs.

Inhibitory Efficacy of Main Components of Scutellaria baicalensis on the Interaction between Spike Protein of SARS-CoV-2 and Human Angiotensin-Converting Enzyme II

“…For the hACE2/S-RBD of the Delta variant, Song et al [ 51 ] found that baicalein interacts with Asp30, Lys26, Leu29, Asn33, Glu96, Pro389, Gln388, Ala387, Thr92, Val93, and Asn90 residues. Shakhsi-Niaei et al [ 52 ] reported that baicalin is a candidate that is able to occupy hACE2 and inhibit viral RBD binding, i.e., baicalin is a strong inhibitor of the SARS-CoV-2 binding site of ACE2. The results of this molecular simulation study showed that baicalin interacts with the active site through three hydrogen bonds with A396, E208, and D206.…”

“…The results of this molecular simulation study showed that baicalin interacts with the active site through three hydrogen bonds with A396, E208, and D206. Many scientists are currently studying the possibility of developing molecules, for example, those based on baicalein and baicalin from S. baicalensis , as effective antiviral drugs [ 24 , 33 , 50 , 51 , 52 ].…”

Multicenter, randomized controlled trial of traditional Japanese medicine, kakkonto with shosaikotokakikyosekko, for mild and moderate coronavirus disease patients

“…In silico , multiple components containing in KT and SSKKS were also identified as candidates to have potential inhibitory activities against SARS-CoV-2. The crude drugs with such potential activities include Bupleurum root, Scutellaria root, Glycyrrhiza ( Hejazi et al, 2021 ; Shakhsi-Niaei et al, 2021 ; Yu et al, 2021 ), Ginger ( Teng et al, 2021 ; Zubair et al, 2021 . ), Pueraria root ( Pan et al, 2020 ), Ephedra herb ( Lv et al, 2021 ), and Cinnamon bark ( Prasanth et al, 2021 ; Husain et al, 2022 .).…”

Revisiting liquorice (Glycyrrhiza glabra L.) as anti-inflammatory, antivirals and immunomodulators: Potential pharmacological applications with mechanistic insight.

“…Moreover, several recent study on G. glabra in combination with standard therapies demonstrated significantly reduction of hospitalization rate and occurrence of COVID-19 symptoms ( Armanini et al, 2020 ; Zhong et al, 2020 ; Gajewski et al, 2021 ; Li et al, 2021a ; 2021b ). Recently, several targets have been identified with the possible interaction of medicinal plants included liquorice a hopeful therapeutic for future drug ( Bandyopadhyay et al, 2021 ; Shakhsi-Niaei et al, 2021 ; Tsai et al, 2021 ). Glycyrrhizin was studied well in past and found to be the most active molecule for inhibition of replication of the SARS-associated virus and can be utilized for treatment of SARS -associated coronavirus ( Cinatl et al, 2003 ).…”