In-silico design of a potential inhibitor of SARS-CoV-2 S protein

Abstract

The SARS-CoV-2 virus has caused a pandemic and is public health emergency of international concern. As of now, no registered therapies are available for treatment of coronavirus infection. The viral infection depends on the attachment of spike (S) glycoprotein to human cell receptor angiotensin-converting enzyme 2 (ACE2). We have designed a protein inhibitor (ΔABP-D25Y) targeting S protein using computational approach. The inhibitor consists of two α helical peptides homologues to protease domain (PD) of ACE2. Docking studies and molecular dynamic simulation revealed that the inhibitor binds exclusively at the ACE2 binding site of S protein. The computed binding affinity of the inhibitor is higher than the ACE2 and thus will likely out compete ACE2 for binding to S protein. Hence, the proposed inhibitor ΔABP-D25Y could be a potential blocker of S protein and receptor binding domain (RBD) attachment.

Peptide and peptide-based inhibitors of SARS-CoV-2 entry

“…As discussed, the entry process of SARS-CoV-2 in human cells is mediated by interactions between S proteins at the surface of the viral membrane and the ACE2 receptor on human cells. Consequently, most computational protocols aimed at preventing the protein – protein interaction between the ACE2 receptor and the RBD domain of the SARS-CoV-2 S proteins [ 53 , [155] , [156] , [157] , [158] , [159] , [160] , [163] , [164] , [165] , [166] ]. The structure of this complex was elucidated early in this year, 2020, and the first coordinates were reported in the Protein Data Bank under the ID codes: 6VW1 [ 167 ], 6 M17 [ 168 ], 6lZG [ 169 ], and 6M0J [ 33 ].…”

“…The structure of this complex was elucidated early in this year, 2020, and the first coordinates were reported in the Protein Data Bank under the ID codes: 6VW1 [ 167 ], 6 M17 [ 168 ], 6lZG [ 169 ], and 6M0J [ 33 ]. Specifically, peptide design strategies mainly focused on extracting candidates based on the ligand binding motif of the ACE2 receptor, and optimizing the sequences of these peptides to obtain potent inhibitors targeting the RBD [ 53 , [155] , [156] , [157] , [158] , [159] , [160] , 163 , 164 , 166 ]. Similarly, efforts have been devoted to the in-silico design of peptide inhibitors targeting the ACE2 receptor [ 165 ] and the HR1 domain of the S protein [ 154 ].…”

“…The computational workflow used in these designs usually comprised well-established techniques such as homology modeling, computational mutagenesis, docking protocols, re-scoring methods and molecular dynamics simulations ( Table 4 ). The applications of these techniques allowed the exploration of peptide libraries [ 158 , [163] , [164] , [165] ] and to build models of new peptides [ 53 , [154] , [155] , [156] , [157] , [158] , [159] , 166 ], as well as the structural and dynamical characterization of the interactions of ACE2 and the peptides with the interface of the viral S protein [ 156 , 160 , 164 , 166 ]. In addition, computational protocols have been used to predict the antiviral activity and the toxicity of peptides with potential inhibitory effect [ 154 , 158 ] ( Table 4 ).…”

“… Purpose Tools To build structural models of new peptide sequences, based on the scaffold of the known Spike-RBD structure, as well as for adding missing fragments in the elucidated structures [ 29 , 53 , 154 , 155 , 157 ] SwissModel [ 51 ], MODELLER [ 191 ] and I-TASSER [ 192 ], and Rosetta [ 193 ] with RIF docking [ 194 ] To reconstruct missing residues and preparing structures for the simulations. Optimizations of rotamers as well as performing minimization procedures and alanine scanning analyses [ 157 , 159 , 160 ] Schrödinger (Prime) [ 195 ], UCSF Chimera software [ 196 ], FoldX [ 197 ] and the proprietary software BIOVIA Discovery Studio [ 198 ], CHARMM-GUI [ 199 ] For peptide – protein docking [ 53 , 154 , 155 , 157 , 163 , 164 , 166 ] HADDOCK [ 200 ], HPEPDOCK [ 201 ], ClusPro [ 202 ], Rosetta [ 193 ], and ZDOCK [ 203 ] Evaluation of the antiviral potential of new peptides and toxicity likelihoods for such peptides [ 154 , 158 ] AVPpred [ 204 ] and AVP-IC50pred [ 205 ] as well as as well as ToxinPred[ 206 ] Re-scoring of the peptide candidates´ affinity to the Spike protein [ 157 ] PRODIGY [ 207 ] Peptide – protein interaction energies and free energy changes [ 154 , …”

A potential peptide inhibitor of SARS-CoV-2 S and human ACE2 complex

“…These residues may be active (interacting residue) or passive (nearby interacting residue). The binding interface of RBD and peptides were predicted using CPORT (de Vries & Bonvin, 2011 ) and BIPSPI (Sanchez-Garcia et al., 2019 ) servers as described previously (Jaiswal & Kumar, 2020 ). Before docking protocol, the pdbs were ‘cleaned’ by removing water and non-bonded ions in a text editor.…”