Identification of potent inhibitors against transmembrane serine protease 2 for developing therapeutics against SARS-CoV-2.

In viral binding and entry, the Spike(S) protein of SARS-CoV-2 uses transmembrane serine protease 2 (TMPRSS2) for priming to cleavage themselves. In this study, we have screened 'drug-like' 7476 ligands and found that over thirty ligands can effectively inhibit the TMPRSS-2 better than the control ligand. Finally, the three best drug agents L1, L2, and L6 were selected according to their average binding affinities and fitting score. These ligands interact with Asp435, Cys437, Ser436, Trp461, and Cys465 amino acid residues. The three best candidates and a reported drug Nafamostat mesylate (NAM) were selected to run 250 ns molecular dynamics (MD) simulations. Various properties of ligand-protein interactions obtained from MD simulation such as bonds, angle, dihedral, planarity, coulomb, and van der Waals (VdW) were used for principal component analysis (PCA) calculation. PCA discloses the evidence of the structural similarities to the corresponding complexes of L1, L2, and L6 with the complex of TMPRSS2(TM) and Nafamostat mesylate (TM-NAM). Moreover, Quantitative structure-activity relationship (QSAR) pattern recognition was generated using PCA for the investigation of structural similarities among the selected ligands. Multiple Linear Regression (MLR) model was built to predict the binding energy compared to the binding energy obtained from molecular docking. The MLR regression model reveals an accuracy of 80% for the prediction of the binding energy of ligands. ADMET analysis demonstrates that these drug agents are appeared to be safer inhibitors. These three ligands can be used as potential inhibitors against the TMPRSS2.Communicated by Ramaswamy H. Sarma.

Large scale peptide screening against main protease of SARS CoV-2.

The COVID-19 pandemic has been a public health emergency, with deadly forms constantly emerging around the world, highlighting the dire need for highly effective antiviral therapeutics. Peptide therapeutics show significant potential for this viral disease due to their efficiency, safety, and specificity. Here, two thousand seven hundred eight antibacterial peptides were screened computationally targeting the Main protease (Mpro) of SARS CoV-2. Six top-ranked peptides according to their binding scores, binding pose were investigated by molecular dynamics to explore the interaction and binding behavior of peptide-Mpro complexes. The structural and energetic characteristics of Mpro-DRAMP01760 and Mpro-DRAMP01808 complexes fluctuated less during a 250 ns MD simulation. In addition, three peptides (DRAMP01760, DRAMP01808, and DRAMP01342) bind strongly to Mpro protein, according to the free energy landscape and principal component analysis. Peptide helicity and secondary structure analysis are in agreement with our findings. Interaction analysis of protein-peptide complexes demonstrated that Mpro's residue CYS145, HIS41, PRO168, GLU166, GLN189, ASN142, MET49, and THR26 play significant contributions in peptide-protein attachment. Binding free energy analysis (MM-PBSA) demonstrated the energy profile of interacting residues of Mpro in peptide-Mpro complexes. To summarize, the peptides DRAMP01808 and DRAMP01760 may be highly Mpro specific, resulting disruption in a viral replication and transcription. The results of this research are expected to assist future research toward the development of antiviral peptide-based therapeutics for Covid-19 treatment.

Repurposing fusion inhibitor peptide against SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously evolving. Although several vaccines were approved, this pandemic is still a major threat to public life. Till date, no established therapies are available against SARS-CoV-2. Peptide inhibitors hold great promise for this viral pathogen due to their efficacy, safety, and specificity. In this study, seventeen antiviral peptides which were known to inhibit SARS-CoV-1 are collected and computationally screened against heptad repeat 1 (HR1) of the SARS-CoV-2 spike protein (S2). Out of 17 peptides, Fp13 and Fp14 showed better binding affinity toward HR1 compared to a control peptide EK1 (a modified pan-coronavirus fusion inhibitor) in molecular docking. To explore the time-dependent interactions of the fusion peptide with HR1, molecular dynamics simulation was performed incorporating lipid membrane. During 100 ns MD simulation, structural and energy parameters of Fp13-HR1 and Fp14-HR1 complexes demonstrated lower fluctuations compared to the control EK1-HR1 complex. Furthermore, principal component analysis and free energy landscape study revealed that these two peptides (Fp13 and Fp14) strongly bind to the HR1 with higher affinity than that of control EK1. Tyr917, Asn919, Gln926, lys933, and Gln949 residues in HR1 protein were found to be crucial residues for peptide interaction. Notably, Fp13, Fp14 showed reasonably better binding free energy and hydrogen bond contribution than that of EK1. Taken together, Fp13 and Fp14 peptides may be highly specific for HR1 which can potentially prevent the formation of the fusion core and could be further developed as therapeutics for treatment or prophylaxis of SARS-CoV-2 infection.