Integrated analysis of usnic acid as a potential inhibitor of dengue NS2B/NS3 protease: DFT, molecular docking, MEP, ADMET, and drug-likeness evaluation

Background: The present study aimed to evaluate the inhibitory capability of 10 pyrazole-usnic acid derivatives against dengue virus serotype 2 (DENV-2) NS2B/NS3 serine protease. The crystallographic structure model of the protease enzyme (PDB code: 2FOM) was used to conduct molecular docking studies of pyrazole-usnic acid derivatives with target proteins. Computational analysis was performed using the Molecular Operating Environment program, Gaussian View software, and ADMETLab platform. Materials and methods: The inhibitory potential of the derivatives was tested by molecular docking using panduratin A as the positive control, together with density functional theory, molecular electrostatic potential analysis, drug-likeness assessment, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling. Results: Among the tested derivatives, compounds 5 and 6 exhibited the most promising inhibitory effects against DENV-2 NS2B/NS3 serine protease. The binding free energy values for these compounds were -7.320 and -7.477 kcal/mol, respectively. These two compounds shared multiple amino acid residues with panduratin A, which was used as a reference inhibitor. Compounds 5 and 6 also displayed negative electrostatic regions surrounding their oxygen atoms, with gap energies of 0.133 and 0.137 eV and dipole moment values of 3.237 and 2.806 D, respectively. Conclusions: These computational findings suggest that compounds 5 and 6 may serve as preliminary candidates for dengue virus inhibition. However, further clinical and experimental studies are required to confirm their efficacy and safety.