Naslov
Pathway enrichment analysis of virus-host interactome and prioritization of novel compounds targeting the spike glycoprotein receptor binding domain-human angiotensin-converting enzyme 2 interface to combat SARSCoV-2

Autori
Pavan, Gollapalli ; Sharath, Belenahalli Shekarappa ; Rimac, Hrvoje ; Patil, Prakash ; Kumari Nalilu, Suchetha ; Kandagalla, Shivanandha ; Shetty, Praveenkumar

Izvornik
Journal of biomolecular structure & dynamics (0739-1102) 40 (2022), 6; 2701-2714

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
SARS-CoV-2 ; protein–protein interactions (PPIs) ; spike glycoprotein ; virtual screening ; molecular docking ; molecular dynamics

Sažetak
SARS-CoV-2 has become a pandemic causing a serious global health concern. The absence of effective drugs for treatment of the disease has caused its rapid spread on a global scale. Similarly to the SARSCoV, the SARS-CoV-2 is also involved in a complex interplay with the host cells. This infection is characterized by a diffused alveolar damage consistent with the Acute Respiratory Disease Syndrome (ARDS). To explore the complex mechanisms of the disease at the system level, we used a network medicine tools approach. The protein-protein interactions (PPIs) between the SARS-CoV and the associated human cell proteins are crucial for the viral pathogenesis. Since the cellular entry of SARS-CoV-2 is accomplished by binding of the spike glycoprotein binding domain (RBD) to the human angiotensin-converting enzyme 2 (hACE2), a molecule that can bind to the spike RDB-hACE2 interface could block the virus entry. Here, we performed a virtual screening of 55 compounds to identify potential molecules that can bind to the spike glycoprotein and spike-ACE2 complex interface. It was found that the compound ethyl 1-f3-[(2, 4-dichlorobenzyl) carbamoyl]-1- ethyl-6-fluoro-4-oxo-1, 4-dihydro-7-quinolinylg-4- piperidine carboxylate (the S54 ligand) and ethyl 1-f3-[(2, 4-dichlorobenzyl) carbamoyl]-1-ethyl-6- fluoro-4-oxo-1, 4-dihydro-7-quinolinylg-4 piperazine carboxylate (the S55 ligand) forms hydrophobic interactions with Tyr41A, Tyr505B and Tyr553B, Leu29A, Phe495B, respectively of the spike glycoprotein, the hotspot residues in the spike glycoprotein RBD-hACE2 binding interface. Furthermore, molecular dynamics simulations and free energy calculations using the MM-GBSA method showed that the S54 ligand is a stronger binder than a known SARS-CoV spike inhibitor SSAA09E3 (N- (9, 10-dioxo-9, 10-dihydroanthracen-2- yl)benzamide).

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija, Interdisciplinarne prirodne znanosti, Farmacija

POVEZANOST RADA