In Silico Drug Repositioning Against Human NRP1 to Block SARS-CoV-2 Host Entry

Abstract

Despite COVID-19 turned into a pandemic, no approved drug for the treatment or globally available vaccine is out yet. In such a global emergency, drug repurposing approach that bypasses a costly and long-time demanding drug discovery process is an effective way in search of finding drugs for the COVID-19 treatment. Recent studies showed that SARS-CoV-2 uses neuropilin-1 (NRP1) for host entry. Here I took advantage of structural information of the NRP1 in complex with C-terminal of spike (S) protein of SARS-CoV-2 to identify drugs that may inhibit NRP1 and S protein interaction. U.S. Food and Drug Administration (FDA) approved drugs were screened using docking simulations. Among top drugs, well-tolerated drugs were selected for further analysis. Molecular dynamics (MD) simulations of drugs-NRP1 complexes were run for 100 ns to assess the persistency of binding. MM/GBSA calculations from MD simulations showed that eltrombopag, glimepiride, sitagliptin, dutasteride, and ergotamine stably and strongly bind to NRP1. In silico Alanine scanning analysis revealed that Tyr<sup>297</sup>, Trp<sup>301</sup>, and Tyr<sup>353</sup> amino acids of NRP1 are critical for drug binding. Validating the effect of drugs analyzed in this paper by experimental studies and clinical trials will expedite the drug discovery process for COVID-19.

Interfering effects on the bioactivities of several key proteins of COVID-19/variants in diabetes by compounds from Lianqiao leaves: In silico and in vitro analyses

“…AutoDock Vina [29] was used for molecular docking. There are eight kinds of proteins involved in docking, namely SARS-RBD-hACE2 (PDB ID: 2AJF ) [30] , SARS-CoV-2-RBD-hACE2 (PDB ID: 6VW1 ) [31] , and Alpha (B.1.1.7), Beta (B.1.351) and Delta (B.1.617) completed in 2.3.1, and M Pro (PDB ID: 6LU7 ) [3] , NRPI (PDB ID: 6FMC ) [32] , PNF1 (PDB ID: 3NUL ) [33] from the RCSB protein database. Small-molecule ligands of forsythoside A (CID: 5281773), forsythoside E (CID: 69634125), veklury (CID: 121304016), chlorogenic acid (CID: 1794427), phillyrin (CID: 101712), umifenovir (CID: 131411), and hydroxychloroquine (CID: 12947) were obtained from NCBI database ( http://www.ncbi.nlm.nih.gov/pccompound ).…”