Targeting the PEDV 3CL protease for identification of small molecule inhibitors: an insight from virtual screening, ADMET prediction, molecular dynamics, free energy landscape, and binding energy calculations

Rajesh Kumar Pathak; Won-Il Kim; Jun-Mo Kim

doi:10.1186/s13036-023-00342-y

Targeting the PEDV 3CL protease for identification of small molecule inhibitors: an insight from virtual screening, ADMET prediction, molecular dynamics, free energy landscape, and binding energy calculations

J Biol Eng. 2023 Apr 18;17(1):29. doi: 10.1186/s13036-023-00342-y.

Authors

Rajesh Kumar Pathak¹, Won-Il Kim², Jun-Mo Kim³

Affiliations

¹ Department of Animal Science and Technology, Chung-Ang University, Anseong-si, Gyeonggi-do 17546, Republic of Korea.
² College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeollabuk-do 54596, Republic of Korea.
³ Department of Animal Science and Technology, Chung-Ang University, Anseong-si, Gyeonggi-do 17546, Republic of Korea. junmokim@cau.ac.kr.

Abstract

Background: The porcine epidemic diarrhea virus (PEDV) represents a major health issue for piglets worldwide and does significant damage to the pork industry. Thus, new therapeutic approaches are urgently needed to manage PEDV infections. Due to the current lack of a reliable remedy, this present study aims to identify novel compounds that inhibit the 3CL protease of the virus involved in replication and pathogenesis.

Results: To identify potent antiviral compounds against the 3CL protease, a virtual screening of natural compounds (n = 97,999) was conducted. The top 10 compounds were selected based on the lowest binding energy and the protein-ligand interaction analyzed. Further, the top five compounds that demonstrated a strong binding affinity were subjected to drug-likeness analysis using the ADMET prediction, which was followed by molecular dynamics simulations (500 ns), free energy landscape, and binding free energy calculations using the MM-PBSA method. Based on these parameters, four putative lead (ZINC38167083, ZINC09517223, ZINC04339983, and ZINC09517238) compounds were identified that represent potentially effective inhibitors of the 3CL protease.

Conclusion: Therefore, these can be utilized for the development of novel antiviral drugs against PEDV. However, this requires further validation through in vitro and in vivo studies.

Keywords: MD simulation; PEDV; Pig; Veterinary drug; Virtual screening.

Abstract

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