Taufik Muhammad Fakih, Ritmaleni, Rahadian Zainul, Muchtaridi Muchtaridi
In the effort to combat SARS-CoV-2 infection, researchers are currently exploring the repurposing of conventional antiviral drugs, despite their limited efficacy. The SARS-CoV-2 virus encodes a papain-like protease (PLpro), which not only plays a crucial role in viral replication but also cleaves ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host proteins, making it a prime target for the development of new antiviral medications. In this study, we conducted a multi-step in silico screening to identify novel, noncovalent PLpro inhibitors. Curcumin, an antioxidant derived from turmeric rhizomes (Curcuma longa L.), has undergone extensive preclinical investigations and shown significant efficacy against viruses and other ailments in both laboratory and animal studies. However, the pharmacological limitations of curcumin have prompted the synthesis of numerous novel curcumin analogs, necessitating evaluation for their therapeutic potential. The selectivity of the top-scoring compounds was assessed through molecular docking studies and molecular dynamics simulations to determine their binding affinity to PLpro. As a result, we identified 20 potential, selective PLpro inhibitors, from which the top two compounds (THA111 and THHGV6) were selected based on their binding free energy values towards PLpro as estimated by MM-PBSA calculations. These selected candidates demonstrate promising activity against the protein, with binding free energy values ranging from approximately −105 to −108 kJ/mol, and largely adopt a similar binding mode to known noncovalent SARS-CoV-2 PLpro inhibitors (GRL0617 = −100.98 kJ/mol). We further propose these two most promising compounds for future in vitro evaluation. The findings for the top potential PLpro inhibitors have been deposited in a database (Curcumin Research Center) to aid research on anti-SARS-CoV-2 drugs. Copyright Fakih TM et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung Sumedang KM 21, Sumedang, 45363, Indonesia; Department of Pharmacy, Faculty of Mathematics and Natural Sciences, Universitas Islam Bandung, Jl. Ranggagading, Bandung, 40116, Indonesia; Laboratory of Medicinal Chemistry, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Jl. Sekip Utara, Yogyakarta, 55281, Indonesia; Curcumin Research Center, Faculty of Pharmacy, Universitas Gadjah Mada, Jl. Sekip Utara, Yogyakarta, 55281, Indonesia; Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Negeri Padang, Jl. Prof Dr Hamka Kampus Air Tawar, Padang, 25131, Indonesia; Research Collaboration Centre for Theranostic Radio Pharmaceuticals, National Research and Innovation Agency (BRIN), Jl. Raya Bandung Sumedang KM 21, Sumedang, 45363, Indonesia
