Identification of promising antiviral drug candidates against non-structural protein 15 (NSP15) from SARS-CoV-2: an in silico assisted drug-repurposing study (original) (raw)
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Potential SARS-CoV-2 Nonstructural Protein 15 (NSP15) Inhibitors: Repurposing FDA-Approved Drugs
2021
Purpose: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of deaths worldwide, pushing the urgent need for an efficient treatment. Nonstructural protein 15 (NSP15) is a promising target due to its importance for SARS-CoV-2’s evasion of the host’s innate immune response. Methods: Using the crystal structure of SARS-CoV-2 NSP15 endoribonuclease, we developed a pharmacophore model of the functional centers in the NSP15 inhibitor’s binding pocket. With this model, we conducted data mining of the conformational database of FDA-approved drugs. The conformations of these compounds underwent 3D fingerprint similarity clustering, and possible conformers were docked to the NSP15 binding pocket. We also simulated docking of random compounds to the NSP15 binding pocket for comparison. Results: This search identified 170 compounds as potential inhibitors of SARS-CoV-2 NSP15. The mean free energy of docking for the group of potential inhibitors were significantly l...
Archives of Biochemistry and Biophysics, 2021
In the current study, a structure-based virtual screening paradigm was used to screen a small molecular database against the Non-structural protein 15 (Nsp15) endoribonuclease of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 is the causative agent of the recent outbreak of coronavirus disease 2019 (COVID-19) which left the entire world locked down inside the home. A multi-step molecular docking study was performed against antiviral specific compounds (~8722) collected from the Asinex antiviral database. The less or non-interacting molecules were wiped out sequentially in the molecular docking. Further, MM-GBSA based binding free energy was estimated for 26 compounds which shows a high affinity towards the Nsp15. The drug-likeness and pharmacokinetic parameters of all 26 compounds were explored, and five molecules were found to have an acceptable pharmacokinetic profile. Overall, the Glide-XP docking score and Prime-MM-GBSA binding free energy of the selected molecules were explained strong interaction potentiality towards the Nsp15 endoribonuclease. The dynamic behavior of each molecule with Nsp15 was assessed using conventional molecular dynamics (MD) simulation. The MD simulation information was strongly favors the Nsp15 and each identified ligand stability in dynamic condition. Finally, from the MD simulation trajectories, the binding free energy was estimated using the MM-PBSA method. Hence, the proposed final five molecules might be considered as potential Nsp15 modulators for SARS-CoV-2 inhibition.
2021
Background: The severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) is a grave global threat causing Coronavirus Disease 2019 (COVID-19). The therapeutics are urgently needed to cure patients severely infected with COVID-19. The aim of the study was to investigate for potential candidates of nsp12 inhibitors by searching for druggable cavity pockets within the viral protein and drug discovery.Methods: The crystallographic structure of SARS-CoV-2 nsp12 was searched for strong druggable cavity pockets and pharmacophore features by the CavityPlus server. The features were selected for high-throughput screening (HTS) of a chemical library of ZINC natural products and hit identification database by ZINCPharmer. Autodock Vina was furthered utilized for estimation of hits' affinities to nsp12. A lead compound with the highest affinity to nsp12 was simulated dynamically by GROMACS for 10 nanoseconds (ns) to measure the hit stability in complex with nsp12 and conformational chan...
Journal of Proteins and Proteomics
COVID-19, the current global pandemic has caused immense damage to human lives and the global economy. It is instigated by the SARS-CoV-2 virus and there is an immediate need for the identification of effective drugs against this deadly virus. SARS-CoV-2 genome codes for four structural proteins, sixteen non-structural proteins (NSPs) and several accessory proteins for its survival inside the host cells. In the present study, through in silico approaches, we aim to identify compounds that are effective against the four NSPs namely, NSP1, NSP4, NSP6 and NSP13 of SARS-CoV-2. The selection criteria of these four NSP proteins are they are least explored and potential targets. First, we have modeled the 3D structures of these proteins using homology modeling methods. Further, through molecular docking studies, we have screened the FDA-approved compounds against these modeled proteins and reported their docking scores. To gain dynamic insights, molecular dynamics studies have also been carried out for the best scored ligand against the NSPs. This study can further pave way for exposing more number of compounds against these proteins and enhance COVID-19 treatment.
Journal of Receptors and Signal Transduction
Recently, a pathogen has been identified as a novel coronavirus (SARS-CoV-2) and found to trigger novel pneumonia (COVID-19) in human beings and some other mammals. The uncontrolled release of cytokines is seen from the primary stages of symptoms to last acute respiratory distress syndrome (ARDS). Thus, it is necessary to find out safe and effective drugs against this deadly coronavirus as soon as possible. Here, we downloaded the three-dimensional model of NSP10/NSP16 methyltransferase (PDB-ID: 6w6l) and main protease (PDB-ID: 6lu7) of COVID-19. Using these molecular models, we performed virtual screening with our anti-viral, inti-infectious, and anti-protease compounds, which are attractive therapeutics to prevent infection of the COVID-19. We found that top screened compound binds with protein molecules with good dock score with the help of hydrophobic interactions and hydrogen bonding. We observed that protease complexed with Cyclocytidine hydrochloride (anti-viral and anti-cancer), Trifluridine (anti-viral), Adonitol, and Meropenem (anti-bacterial), and Penciclovir (anti-viral) bound with a good docking score ranging from À6.8 to À5.1 (Kcal/mol). Further, NSP10/ NSP16 methyltransferase complexed with Telbivudine, Oxytetracycline dihydrate (anti-viral), Methylgallate (anti-malarial), 2-deoxyglucose and Daphnetin (anti-cancer) from the docking score of À7.0 to À5.7 (Kcal/mol). In conclusion, the selected compounds may be used as a novel therapeutic agent to combat this deadly pandemic disease, SARS-CoV-2 infection, but needs further experimental research. HIGHLIGHTS NSP10/NSP16 methyltransferase and main protease complex of SARS CoV-2 bind with selected drugs. NSP10/NSP16 methyltransferase and protease interacted with drugs by hydrophobic interactions. Compounds show good DG binging free energy with protein complexes. Ligands were found to follow the Lipinski rule of five.
Biomolecules
The SARS-CoV-2 non-structural protein (nsp) nsp10–nsp16 complex is essential for the 2′-O-methylation of viral mRNA, a crucial step for evading the innate immune system, and it is an essential process in SARS-CoV-2 life cycle. Therefore, detecting molecules that can disrupt the nsp10–nsp16 interaction are prospective antiviral drugs. In this study, we screened the North African Natural Products database (NANPDB) for molecules that can interact with the nsp10 interface and disturb the nsp10–nsp16 complex formation. Following rigorous screening and validation steps, in addition to toxic side effects, drug interactions and a risk /benefit assessment, we identified four compounds (genkwanin-6-C-beta-glucopyranoside, paraliane diterpene, 4,5-di-p-trans-coumaroylquinic acid and citrinamide A) that showed the best binding affinity and most favourable interaction with nsp10 interface residues. To understand the conformational stability and dynamic features of nsp10 bound to the four selecte...
Biochemical Journal
SARS-CoV-2 is responsible for COVID-19, a human disease that has caused over 2 million deaths, stretched health systems to near-breaking point and endangered economies of countries and families around the world. Antiviral treatments to combat COVID-19 are currently lacking. Remdesivir, the only antiviral drug approved for the treatment of COVID-19, can affect disease severity, but better treatments are needed. SARS-CoV-2 encodes 16 non-structural proteins (nsp) that possess different enzymatic activities with important roles in viral genome replication, transcription and host immune evasion. One key aspect of host immune evasion is performed by the uridine-directed endoribonuclease activity of nsp15. Here we describe the expression and purification of nsp15 recombinant protein. We have developed biochemical assays to follow its activity, and we have found evidence for allosteric behaviour. We screened a custom chemical library of over 5000 compounds to identify nsp15 endoribonucleas...
Repurposed drug molecules targeting NSP12 protein of SARS-CoV-2: An in-silico study
AIMS Molecular Science, 2023
The emergence of SARS-CoV-2 created a havoc worldwide, causing high morbidity, serious complications and mortality. The ORF1ab of SARS-CoV-2 has 16 non-structural proteins which are required for genome replication and transcription. All of these are druggable targets, of which NSP12 (RNA-dependent RNA polymerase), was selected as a potential target for drug molecules. Remdesivir is a recommended drug for SARS-CoV-2 and it targets the RdRp protein. Although Remdesivir was given to COVID-19 patients based on their clinical manifestations, yet the transmission and spread of the virus continued and to add to its pandemicity, new variants emerged from time to time. This necessitates the need for molecular modification of existing antiviral drugs so that more precise targets for halting viral replication can be selected. For this, the approach used was repurposing of the existing drugs. In the present study, ten FDA-approved drugs were chosen on the basis of their properties of inhibiting the RdRp protein. These drugs were subjected for checking the docking score with the target protein. Of these, Remdesivir, Ribavirin, Favipiravir and Baloxavir were taken for further analysis on the basis of their best scores. These drugs were then modified to check the efficiency to inhibit the RdRp and to stop the replication rate of the virus. We docked the modified drugs with the macrodomain 323 of RdRp by using the CB-Dock web server and checked the binding affinity and amino acid contact residues. The modified drugs were also checked for bioactivity in the Molinspiration cheminformatics online tool. Our results showed increased affinity for RdRp of SARS-CoV-2 when compared to the original compound. We also checked the synthetic accessibility of the drugs using the SwissADME tool. The study showed promising results when modified. The findings reported need further confirmation through wet lab studies. Keywords: SARS-CoV-2; remdesivir; RdRp; respiratory drugs; docking; MD simulation
Journal of Biomolecular Structure and Dynamics, 2020
In this study, the Nsp12-Nsp8 complex of SARS-CoV-2 was targeted with structure-based and computer-aided drug design approach because of its vital role in viral replication. Sequence analysis of RNA-dependent RNA polymerase (Nsp12) sequences from 30,366 different isolates were analysed for possible mutations. FDA-approved and investigational drugs were screened for interaction with both mutant and wild-type Nsp12-Nsp8 interfaces. Sequence analysis revealed that 70.42% of Nsp12 sequences showed conserved P323L mutation, located in the Nsp8 binding cleft. Compounds were screened for interface interaction, any with XP GScores lower than À7.0 kcal/mol were considered as possible interface inhibitors. RX-3117 (fluorocyclopentenyl cytosine) and Nebivolol had the highest binding affinities in both mutant and wild-type enzymes, therefore they were selected and resultant protein-ligand complexes were simulated for analysis of stability over 100 ns. Although the selected ligands had partial mobility in the binding cavity, they were not removed from the binding pocket after 100 ns. The ligand RX-3117 remained in the same position in the binding pocket of the mutant and wild-type enzyme after 100 ns MD simulation. However, the ligand Nebivolol folded and embedded in the binding pocket of mutant Nsp12 protein. Overall, FDA-approved and investigational drugs are able to bind to the Nsp12-Nsp8 interaction interface and prevent the formation of the Nsp12-Nsp8 complex. Interruption of viral replication by drugs proposed in this study should be further tested to pave the way for in vivo studies towards the treatment of COVID-19.
Network Modeling Analysis in Health Informatics and Bioinformatics
An outbreak of a cluster of viral pneumonia cases, subsequently identified as coronavirus disease 2019 (COVID-19), due to a novel SARS-CoV-2 necessitates an urgent need for a vaccine to prevent infection or an approved medication for a cure. In our in silico molecular docking study, a total of 173 compounds, including FDA-approved antiviral drugs, with good ADME descriptors, and some other nucleotide analogues were screened. The results show that these compounds demonstrate strong binding affinity for the residues at the active sites of RNA-dependent RNA-polymerase (RdRp) modelled structures and Chymotrypsin-like cysteine protease (3CLpro) of the HCoV proteins. Free energies (ΔG's) of binding for SARS-CoV-2 and SARS-CoV RdRp range from-5.4 to-8.8 kcal/mol and-4.9 to-8.7 kcal/mol, respectively. Also, SARS-CoV-2 and SARS-CoV 3CLpro gave ΔG values ranging from − 5.1 to − 8.4 kcal/mol and − 5.5 to − 8.6 kcal/mol, respectively. Interesting results are obtained for ivermectin, an antiparasitic agent with broad spectrum activity, which gave the highest binding energy value (− 8.8 kcal/mol) against the 3CLpro of SARS-CoV-2 and RdRps of both SARS-CoV and SARS-CoV-2. The reason for such high binding energy values is probably due to the presence of hydroxy, methoxy and sugar moieties in its structure. The stability of the protein-ligand complexes of polymerase inhibitors considered in this investigation, such as Sofosbuvir, Remdesivir, Tenofovir, Ribavirin, Galidesivir, 5c3, 5h1 and 7a1, show strong to moderate hydrogen bonding and hydrophobic interactions (π-π stacked, π-π T-shaped, π-sigma and π-alkyl). The stability provided from such interactions translate into greater antiviral activity or inhibitory effect of the ligands. Assessment of the average free energies of binding of the FDA approved drugs are highly comparable for conformers of a particular inhibitor, indicating similar modes of binding within the pockets.