LitCovid-sentences  

PMC:7094172 / 10119-13326 JSONTXT 14 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T75 0-74 Sentence denotes Direct Targeting of the Non-native Dimer Interface for Antiviral Screening
T76 75-198 Sentence denotes We performed a structure-based virtual screening by targeting W43 in the hydrophobic pocket of the N-NTD dimeric interface.
T77 199-386 Sentence denotes H37 and M38 were removed from the template to identify compounds that could replace the vector-fusion residues and, therefore, contribute to the stabilizing effect (Figures 2A and S2A,B).
T78 387-552 Sentence denotes We chose the highest-scoring hits, listed in Table S2, based on shape complementarity, the presence of aromatic moieties, and the ability to stack onto W43 of N-NTD.
T79 553-954 Sentence denotes Because the formation of the non-native dimers was primarily mediated by hydrophobic interactions in our structure (Figure 1C,D), we next considered the hydrophobic complementarity between the acquired ligands and N-NTD in the form of the lipophilic match surface (SL/L).31 We also took into account the ability of the drug to permeate cells by aiming for lower topological polar surface areas (TPSA).
T80 955-1038 Sentence denotes Based on the above criteria, three compounds were finally chosen for further study.
T81 1039-1169 Sentence denotes Benzyl-2-(hydroxymethyl)-1-indolinecarboxylate (P1) and 5-benzyloxygramine (P3) had higher SL/L and docking scores and lower TPSA.
T82 1170-1250 Sentence denotes The clinical drug etodolac (P2) had a comparable SL/L but a lower docking score.
T83 1251-1286 Sentence denotes It too was selected as a candidate.
T84 1287-1669 Sentence denotes However, only P3 induced a comparatively larger blue shift in the intrinsic N-NTD fluorescence spectrum, indicating that the microenvironment surrounding the tryptophans of the protein increased in rigidity and hydrophobicity in the presence of P3.32 The result also indicated that P3 bound more tightly to the N protein than P1 or P2 by interacting with the W43 pocket (Figure 2B).
T85 1670-1814 Sentence denotes Fluorescent thermal stability assays disclosed that the N-NTD denaturation melting temperature had increased from 42 to 45 °C when P3 was added.
T86 1815-1892 Sentence denotes The sigmoidal melting curve for MERS-CoV N-NTD changed in the presence of P3.
T87 1893-2002 Sentence denotes The delay in protein denaturation suggests that P3 stabilized the MERS-CoV N-NTD dimer structure (Figure 2C).
T88 2003-2151 Sentence denotes We then measured the cytotoxic concentration (CC50) and effective concentration (EC50) for each compound using Vero E6 cells infected with MERS-CoV.
T89 2152-2254 Sentence denotes Table 1 shows that P3 had a favorable therapeutic index among the lead compounds tested in this study.
T90 2255-2322 Sentence denotes Therefore, P3 is an excellent candidate inhibitor against MERS-CoV.
T91 2323-2492 Sentence denotes Figure 2 Compound P3 was a potent stabilizer of the MERS-CoV N protein. (A) Schematic depicting the rationale used in designing the allosteric stabilizer of this study.
T92 2493-2855 Sentence denotes An orthosteric stabilizer may be used to bind to the non-native interaction interface of the N protein and stabilize the abnormal interaction between proteins. (B) Conformation and (C) stability analyses were performed based on the FL spectra of NTD (1 μM) incubated with P1–P3 (10 μM) for 1 h with a buffer consisting of 50 mM Tris-HCl (pH 8.3) and 150 mM NaCl.
T93 2856-2920 Sentence denotes Table 1 CC50 and EC50 and Therapeutic Indexes of Lead Compounds
T94 2921-2960 Sentence denotes quantal dose–response relationship (μM)
T95 2961-3000 Sentence denotes compound CC50a EC50b TIc (CC50/EC50)
T96 3001-3022 Sentence denotes P1 459.69 >100 NAd
T97 3023-3044 Sentence denotes P2 569.77 >100 NAd
T98 3045-3067 Sentence denotes P3 805.32 32.1 25.1
T99 3068-3076 Sentence denotes a CC50:
T100 3077-3113 Sentence denotes Half maximal toxicity concentration.
T101 3114-3122 Sentence denotes b EC50:
T102 3123-3160 Sentence denotes Half maximum effective concentration.
T103 3161-3167 Sentence denotes c TI:
T104 3168-3186 Sentence denotes Therapeutic index.
T105 3187-3193 Sentence denotes d NA:
T106 3194-3207 Sentence denotes Nonavailable.