Natural Compound ZINC12899676 Reduces Porcine Epidemic Diarrhea Virus Replication by Inhibiting the Viral NTPase Activity

Abstract

Porcine epidemic diarrhea virus (PEDV) is an alphacoronavirus (α-CoV) that causes high mortality in suckling piglets, leading to severe economic losses worldwide. No effective vaccine or commercial antiviral drug is readily available. Several replicative enzymes are responsible for coronavirus replication. In this study, the potential candidates targeting replicative enzymes (PLP2, 3CLpro, RdRp, NTPase, and NendoU) were screened from 187,119 compounds in ZINC natural products library, and seven compounds had high binding potential to NTPase and showed drug-like property. Among them, ZINC12899676 was identified to significantly inhibit the NTPase activity of PEDV by targeting its active pocket and causing its conformational change, and ZINC12899676 significantly inhibited PEDV replication in IPEC-J2 cells. It first demonstrated that ZINC12899676 inhibits PEDV replication by targeting NTPase, and then, NTPase may serve as a novel target for anti-PEDV.

Creating NADP+‐Specific Formate Dehydrogenases from Komagataella phaffii by Enzymatic Engineering

“…In addition, the binding affinity of Kph FDH/V19 and NADP + were quantified by calculating the free binding energy from the stable 40–50 ns trajectory based on the Molecular Mechanics Poisson‐Boltzmann Surface Area (MM‐PBSA) [31] . Wang et.al indicated that the free binding energy lower than −57 kJ/mol was regarded as a very strong affinity [32] . Consequently, the free binding energy versus time was shown in Figure 5E with an average value of −114.94 kJ/mol, demonstrating a very strong affinity between Kph FDH/V19 and NADP + .…”

“…[31] Wang et.al indicated that the free binding energy lower than À 57 kJ/mol was regarded as a very strong affinity. [32] Consequently, the free binding energy versus time was shown in Figure 5E with an average value of À 114.94 kJ/mol, demonstrating a very strong affinity between KphFDH/V19 and NADP + .…”

“…The APBS 3.0 with the gmx_mmpbsa shell (https://github.com/Jerkwin/gmxtools/gmx_mmpbsa) was used to calculate the free binding energy based on 40–50 ns trajectory. Free binding energy below −57 kJ/mol was perceived to have a very strong affinity [32] …”

A Review of Bioactive Compounds against Porcine Enteric Coronaviruses

“…Further studies showed that these two carbazole derivatives mainly inhibit viral attachment. Wang et al identified that the ZINC natural product ZINC12899676 is able to inhibit PEDV NTPase activity by binding to its active site and changing its active pocket conformation [ 78 ]. Zhou et al screened two compounds targeting PEDV 3CLpro, 3-(aminocarbonyl)-1-phenylpyridinium and 2,3-dichloronaphthoquinone, using a fluorescence resonance energy transfer-based assay [ 79 ].…”