Repurposing of known drugs for COVID-19 using molecular docking and simulation analysis

The study investigates repurposing of known drugs against COVID-19 using computational approaches focused on host and viral targets. Building on prior work suggesting NF-κB suppression (e.g., by Sulindac) may mitigate COVID-19 pathology, the authors screen 51 approved or known bioactive compounds targeting NF-κB-related pathways and other host–virus interaction nodes. The central hypothesis is that host-targeting agents (e.g., NF-κB inhibitors, ACE2/TMPRSS2 binders) may provide robust therapeutic benefit with reduced resistance risk, and that molecular docking and molecular dynamics (MD) simulations can identify stable, high-affinity complexes to prioritize candidates for further validation.

The background highlights the importance of mapping virus–host proteome interactions to identify essential host machinery for SARS-CoV-2 processing, referencing affinity purification and proximity labeling studies that revealed critical host factors and interaction domains/motifs. Prior work suggested methotrexate as a promising host-directed agent. The authors discuss the rationale for host-targeting antivirals to minimize resistance given viral mutation rates, and the role of domains/motifs in viral hijacking of host processes. They also note NF-κB activation in COVID-19 (including cytokine storm and extrapulmonary manifestations) and prior reports on agents such as boswellic acid, GYY-4137, BMS-345541, and other small molecules identified through in silico studies as potential anti–SARS-CoV-2 candidates.

- Targets and structures: Five protein receptors were selected and retrieved as high-resolution X-ray structures from RCSB PDB in .pdb format: 1R42 (ACE2-related carboxypeptidase, 2.2 Å), 4G3D (human NF-κB inducing kinase, 2.9 Å), 6VW1 (SARS-CoV-2 RBD complexed with human ACE2, 2.68 Å), 6VXX (SARS-CoV-2 spike glycoprotein, 2.8 Å), and 7MEQ (human TMPRSS2 in complex with Nafamostat, 1.95 Å). - Ligands: 51 compounds spanning classes including IKK complex inhibitors, IκB degradation inhibitors, NF-κB nuclear translocation inhibitors, p65 acetylation inhibitors, NF-κB DNA-binding/transactivation inhibitors, p53 inducers, and NF-κB activators/inducers were obtained from PubChem and ZINC as .sdf; where needed, 3D structures were generated from SMILES using CORINA. - Docking/virtual screening: Ligands were prepared (Open Babel, Autodock 4.2.6; conversion to .pdbqt; editing with JSME). Docking was performed in PyRx (AutoDock/AutoDock Vina backend) with grid boxes encompassing the entire protein; exhaustiveness set to 8. For each complex, the best-scoring conformer with lowest binding energy and best RMSD was selected. Complexes were visualized in 2D (Maestro, Schrödinger) and 3D (PyMOL export to Discovery Studio). Interactions (H-bonds, hydrophobics) were annotated. - Molecular dynamics simulations: Top complex per receptor (five total) underwent 100 ns MD in Desmond (Schrödinger, Maestro GUI). Protein–ligand complexes were preprocessed (error checks, 500-step steepest descent minimization, water removal). System builder: orthorhombic box with 5 Å buffer; OPLS3e force field; neutralization with Na+/Cl−; pH 7.0 protonation states. Equilibration/production protocol included Brownian dynamics NVT at 10 K and 50 K, NPT at 50 K, followed by NVT productions with constraints removed (200 ps and 500 ps), and production at 310 K with 2 fs timestep; trajectory recorded every 0.1 ns. Analyses included RMSD, protein RMSF, ligand RMSF, protein–ligand contacts (H-bonds, hydrophobics, ionic, water bridges), ligand properties (Rg, MolSA, SASA, PSA, intra-HBs), and secondary structure content.

- Docking highlights (binding energies, kcal/mol): • 1R42 (ACE2-related): Boswellic acid −9.2; Pimecrolimus −9.0; Tacrolimus −9.0; IKK-16 −8.9; Triamcinolone hexacetonide −8.7. • 4G3D (NIK): Pimecrolimus −9.1; Tacrolimus −9.1; GYY_4137 −8.9; IKK-16 −8.9; Boswellic acid −8.6. • 6VW1 (SARS-CoV-2 RBD–ACE2): GYY_4137 −10.3; Triamcinolone acetonide −10.2; Triamcinolone hexacetonide −9.9; Sulindac −9.5; Diacerein −9.4. • 6VXX (S spike): BMS_345541 −10.1; GYY_4137 −9.9; Boswellic acid −9.7; IKK-16 −9.7; Triamcinolone acetonide −9.65. • 7MEQ (TMPRSS2): Triamcinolone hexacetonide −8.7; GYY_4137 −8.7; Mesalamine −8.2; Resveratrol −8.0; Lactacystin −7.8; Sulindac −7.8. - MD stability (protein RMSD, Å): Triamcinolone hexacetonide–7MEQ 2.05; BMS_345541–6VXX 3.38; Boswellic acid–1R42 3.34; GYY_4137–6VW1 13.50; Pimecrolimus–4G3D 25.50. All trajectories equilibrated by ~100 ns; lower RMSD (≤~4 Å) indicated higher stability for ACE2, spike, and TMPRSS2 complexes, whereas higher RMSD for 4G3D and 6VW1 suggested larger conformational changes yet eventual equilibration. - Protein RMSF (Å): Approximate ranges—Boswellic acid–1R42 0.8–7 (peaks ~4.8, 6.4, 7.2); Pimecrolimus–4G3D 3–27; GYY_4137–6VW1 1.5–14 (peaks ~10.5–14); BMS_345541–6VXX 0.8–7.2; Triamcinolone hexacetonide–7MEQ 0.6–5.4 (peak 5.4). - Ligand RMSF: Generally 1–4 Å; Triamcinolone hexacetonide–7MEQ showed 1–2 Å indicative of good fit. - Key interactions during MD: • Boswellic acid–1R42 involved residues Arg273, Phe504, Tyr50, Tyr127, Ile54, Val343, Phe274, Trp271, Asp269, Asn149, Met270; hydrophobics predominated; H-bonds at Asn149, Gly268, Leu503 had high interaction fractions. • Pimecrolimus–4G3D showed hydrophobic contact notably with Leu455; water bridges prevalent; Glu1017 had high H-bond interaction fraction in spike complex (BMS_345541–6VXX). • BMS_345541–6VXX engaged Ala1020 (A/B/C), Asn1023 (B), Glu1027 (A), Ala1016 (B), Ile1013 (A); hydrophobics and water bridges. • GYY_4137–6VW1 engaged Glu406, Glu375, His374, Arg518, Pro346, Leu370, Ser409, Lys363, Phe274; ionic interaction prominent at His374 and multiple contacts at Glu365. • Triamcinolone hexacetonide–7MEQ involved Ser261, Glu260, Ala399, Trp267, Ala266, Trp380, Trp453; multiple persistent contacts at Trp267, Ala399, Asn451, Trp453. - Secondary structure: Boswellic acid–1R42 complex retained more α-helices; BMS_345541–6VXX showed more β-strands. - Overall: Stable binding observed particularly for boswellic acid to ACE2 (1R42), BMS_345541 to spike (6VXX), and triamcinolone hexacetonide to TMPRSS2 (7MEQ), supporting these as repurposing candidates; NF-κB pathway targeting (e.g., pimecrolimus) is supported despite conformational dynamics.

The computational screening and MD analyses support the feasibility of repurposing known drugs to target both host (ACE2, TMPRSS2, NF-κB signaling) and viral (spike) components relevant to SARS-CoV-2 entry and pathogenesis. Stable, high-affinity complexes for boswellic acid with ACE2, BMS_345541 with spike, and triamcinolone hexacetonide with TMPRSS2 suggest possible interference with viral attachment, priming, or fusion. Targeting the NF-κB axis—implicated in cytokine storm and extrapulmonary manifestations—via inhibitors such as pimecrolimus and BMS_345541 aligns with literature indicating immunomodulatory benefits. Although some systems (e.g., GYY_4137–6VW1 and pimecrolimus–4G3D) exhibited larger conformational rearrangements, trajectories equilibrated, implying potential binding robustness. The results provide molecular-level interaction maps (H-bonds, hydrophobics, ionic contacts, water bridges) that rationalize binding efficacy and may guide optimization. Collectively, these findings address the research aim by nominating specific repurposable agents with demonstrated in silico stability and favorable interaction profiles against key COVID-19-relevant targets.

This work identifies several repurposing candidates against COVID-19 using docking and 100 ns MD simulations, notably boswellic acid (ACE2), BMS_345541 (spike), triamcinolone hexacetonide (TMPRSS2), GYY_4137 (RBD–ACE2 complex), and pimecrolimus (NIK/NF-κB pathway). The study underscores the therapeutic potential of host-targeting strategies, including modulation of NF-κB to mitigate hyperinflammation. The authors recommend further experimental validation and clinical studies to confirm efficacy and safety, and suggest future work to evaluate variant robustness, broader host interactomes, and synergistic combinations.

The study is purely in silico, relying on docking scores and MD simulations without experimental (in vitro/in vivo) validation. Some complexes exhibited high protein RMSD and RMSF, indicating substantial conformational changes that may affect binding under physiological conditions. Docking to static structures and limited receptor set may not capture all relevant conformations, post-translational modifications, or variant mutations. Clinical efficacy and safety remain to be established, and the authors explicitly note the need for thorough clinical trials.