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Screening of world approved drugs against highly dynamical spike glycoprotein of SARS-CoV-2 using CaverDock and machine learning.

ABSTRACT: The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes pathological pulmonary symptoms. Most efforts to develop vaccines and drugs against this virus target the spike glycoprotein, particularly its S1 subunit, which is recognised by angiotensin-converting enzyme 2. Here we use the in-house developed tool CaverDock to perform virtual screening against spike glycoprotein using a cryogenic electron microscopy structure (PDB-ID: 6VXX) and the representative structures of five most populated clusters from a previously published molecular dynamics simulation. The dataset of ligands was obtained from the ZINC database and consists of drugs approved for clinical use worldwide. Trajectories for the passage of individual drugs through the tunnel of the spike glycoprotein homotrimer, their binding energies within the tunnel, and the duration of their contacts with the trimer's three subunits were computed for the full dataset. Multivariate statistical methods were then used to establish structure-activity relationships and select top candidate for movement inhibition. This new protocol for the rapid screening of globally approved drugs (4359 ligands) in a multi-state protein structure (6 states) showed high robustness in the rate of finished calculations. The protocol is universal and can be applied to any target protein with an experimental tertiary structure containing protein tunnels or channels. The protocol will be implemented in the next version of CaverWeb (https://loschmidt.chemi.muni.cz/caverweb/) to make it accessible to the wider scientific community.

SUBMITTER: Pinto GP

PROVIDER: S-EPMC8174816 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe receptor binding domain (RBD) of spike protein S1 domain SARS-CoV-2 plays a key role in the interaction with ACE2, which leads to subsequent S2 domain mediated membrane fusion and incorporation of viral RNA into host cells. In this study we tend to repurpose already approved drugs as inhibitors of the interaction between S1-RBD and the ACE2 receptor.Methods2456 approved drugs were screened against the RBD of S1 protein of SARS-CoV-2 (target PDB ID: 6M17). As the interacting surface between S1-RBD and ACE2 comprises of bigger region, the interacting surface was divided into 3 sites on the basis of interactions (site 1, 2 and 3) and a total of 5 grids were generated (site 1, site 2, site 3, site 1+site 2 and site 2+site 3). A virtual screening was performed using GLIDE implementing HTVS, SP and XP screening. The top hits (on the basis of docking score) were further screened for MM-GBSA. All the top hits were further evaluated in molecular dynamics studies. Performance of the virtual screening protocol was evaluated using enrichment studies.Resultand discussion: We performed 5 virtual screening against 5 grids generated. A total of 42 compounds were identified after virtual screening. These drugs were further assessed for their interaction dynamics in molecular dynamics simulation. On the basis of molecular dynamics studies, we come up with 10 molecules with favourable interaction profile, which also interacted with physiologically important residues (residues taking part in the interaction between S1-RBD and ACE2. These are antidiabetic (acarbose), vitamins (riboflavin and levomefolic acid), anti-platelet agents (cangrelor), aminoglycoside antibiotics (Kanamycin, amikacin) bronchodilator (fenoterol), immunomodulator (lamivudine), and anti-neoplastic agents (mitoxantrone and vidarabine). However, while considering the relative side chain fluctuations when compared to the S1-RBD: ACE2 complex riboflavin, fenoterol, cangrelor and vidarabine emerged out as molecules with prolonged relative stability.ConclusionWe identified 4 already approved drugs (riboflavin, fenoterol, cangrelor and vidarabine) as possible agents for repurposing as inhibitors of S1:ACE2 interaction. In-vitro validation of these findings are necessary for identification of a safe and effective inhibitor of S1: ACE2 mediated entry of SARS-CoV-2 into the host cell.

Project description:Japanese encephalitis virus (JEV), an arthropod-borne flavivirus, is a major cause of acute viral encephalitis in humans. No approved drug is available for the specific treatment of JEV infections, and the available vaccines are not effective against all clinical JEV isolates. In the study described here, a high-throughput screening of an FDA-approved drug library for inhibitors of JEV was performed. Five hit drugs that inhibited JEV infection with a selective index of >10 were identified. The antiviral activities of these five hit drugs against other flavivirus, including Zika virus, were also validated. As three of the five hit drugs were calcium inhibitors, additional types of calcium inhibitors that confirmed that calcium is essential for JEV infection, most likely during viral replication, were utilized. Adaptive mutant analysis uncovered that replacement of Q130, located in transmembrane domain 3 of the nonstructural NS4B protein, which is relatively conserved in flaviviruses, with R or K conferred JEV resistance to manidipine, a voltage-gated Ca2+ channel (VGCC) inhibitor, without an apparent loss of the viral growth profile. Furthermore, manidipine was indicated to protect mice against JEV-induced lethality by decreasing the viral load in the brain, while it abrogated the histopathological changes associated with JEV infection. This study provides five antiflavivirus candidates and identifies cytoplasmic calcium to be a novel antiviral target for the treatment of JEV infection. The findings reported here provide therapeutic possibilities for combating infections caused by flaviviruses.IMPORTANCE No approved therapy for the treatment of Japanese encephalitis virus infection is currently available. Repurposing of approved drugs would accelerate the development of a therapeutic stratagem. In this study, we screened a library of FDA-approved drugs and identified five hit drugs, especially calcium inhibitors, exerting antiflavivirus activity that blocked viral replication. The in vivo efficacy and toxicity of manidipine were investigated with a mouse model of JEV infection, and the viral target was identified by generating an adaptive mutant.

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Screening of world approved drugs against highly dynamical spike glycoprotein of SARS-CoV-2 using CaverDock and machine learning.

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