Chromone–Thiophene Hybrids as Non-Peptidic Inhibitors of SARS-CoV-2 Mpro: Integrated ADME, Docking, and Molecular Dynamics Approach

The SARS‑CoV‑2 main protease (Mpro) is indispensable for viral polyprotein maturation and therefore constitutes a prime antiviral drug target. Guided by drug‑likeness metrics, we designed a focused series of chromone‑thiophene derivatives (M1-M4) that combine a rigid, π‑rich chromone core with a sulfur‑containing hydrophobic anchor. SwissADME calculations revealed that progressive hydroxylation (0-2 OH) endows the series with ideal physicochemical parameters (MW 228-260 g mol⁻¹, cLogP 2.5-3.1, TPSA 58-99 Å²) and zero Lipinski/Veber violations, contrasting sharply with the rule‑breaking reference inhibitor ritonavir. Toxicity forecasts with ProTox‑III place all four compounds in acute‑toxicity class 4 with LD₅₀ values of 600-1070 mg kg⁻¹, substantially lower structural uncertainty than ritonavir. Structure‑based docking against the high‑resolution crystal structure of Mpro (PDB 9C8Q) singled out M3 (5‑hydroxy analog) as the only ligand engaging both His163 and Glu166 via dual hydrogen bonds while simultaneously establishing π‑sulfur contacts with Cys44/Cys145 and a π‑cation clamp with His41 (ΔG = ‑6.8 kcal mol⁻¹). A 100 ns all‑atom molecular‑dynamics simulation in TIP3P water confirmed the robustness of this pose: backbone RMSD converged at 0.12 nm, ligand RMSD plateaued at 0.6 nm after an early accommodation phase, and per‑residue RMSF values around the catalytic dyad and S1/S2 pockets remained below 0.12 nm, indicating a “locked” active‑site conformation. Collectively, these multiscale in silico data advocate M3 as a synthetically accessible lead scaffold that couples favorable oral‑drug properties to sustained catalytic‑site engagement, meriting experimental validation against SARS‑CoV‑2 replication.