Design and Virtual Screening of Dihydropyrimidinone and Chromene-Based Derivatives as Potential SARS-CoV-2 NSP16 Methyltransferase Inhibitors

Background: Dihydropyrimidinone (DHPM) and chromene scaffolds are widely recognized as bioactive heterocyclic frameworks frequently found in natural products and known for their structural versatility and synthetic accessibility. Numerous studies have reported diverse pharmacological activities of DHPM and chromene derivatives, including antiviral properties. In our preliminary study, representative DHPM and chromene derivatives, S12 and S10, exhibited antiviral activity against SARS-CoV-2 in cell-based assays (IC_₅₀ = 6.187–8.52 μM), supporting further structural optimization. Objective: This study aimed to perform structure-based virtual screening of DHPM and chromene derivatives based on two antiviral lead compounds identified in our preliminary study (S12 and S10) targeting the SARSCoV- 2 nonstructural protein 16 (NSP16), a 2′-O-methyltransferase involved in viral RNA capping and immune evasion. Materials and Methods: A library of 503 designed derivatives and eight repurposed antiviral drugs as reference compounds were screened against NSP16 (PDB ID: 8F4S). Compound ranking was performed using a Selection Score (SS) integrating docking score, docking pose quality, and predicted pharmacokinetic and toxicity parameters. Consensus docking analysis using DOCK6 and AutoDock Vina was applied to improve the robustness of compound ranking. Results: Several derivatives demonstrated favorable binding interactions within the NSP16 cryptic pocket and acceptable predicted ADMET profiles. Cross-platform docking comparison showed moderate ranking agreement between the two docking engines, supporting the robustness of the prioritization process within a computational framework. Conclusion: Based on the integrated virtual screening approach, two DHPM and one chromene derivatives were identified as prioritized candidates for SARS-CoV-2 NSP16 inhibition and can be further evaluated in experimental studies.