Dehydroacetic Acid-Phenylhydrazone as a Potential Inhibitor for Wild-Type HIV-1 Protease: Structural, DFT, Molecular Dynamics, 3D QSAR and ADMET Characteristics

Despite several studies towards anti-HIV therapy, HIV infections remain a challenge due to the resistivity of developed drugs. The emergence of new HIV-1 PR mutations has led to the drug resistance of the available FDA-approved drugs and lower activity towards the HIV protease. Based on this the molecular properties of 4-hydroxy-6-methyl-3-[(1E)-1-(2-phenylhydrazinylidene) ethyl]- 2H-pyran-2-one (DHAA-PH) has been carried out using the hybrid Density Functional Theory (DFT) and Time-Dependent (TDFT) method at B3LYP/6-31+G(d,p) levels of theory. To substantiate the sensitivity of functional applied M06-2X/ 6-31 1++G(2d,2p) and mPWB1W/6-311++G(2d,2p) was used to calculate the geometric, IR, H-1 NMR, and energy gap calculations. DFT calculations with M06-2X and mPWB1W were observed to agree with the experiment compared to B3LYP functional. The absorption spectra of DHAA-PH showed three distinct bands which were designated as S-0 to S-1, S-0 to S-2, and S-0 to S-3 in order of increasing energy. The high intensity (oscillator strength) of S-0 to S-1 infers that the transition is quantum-mechanically allowed, while the low intensity of S-0 to S-2 and S-0 to S-3 transitions suggests quantum mechanically forbidden transitions. Molecular dynamics simulations revealed that the obtained MMGBSA binding energies are better compared to the experimentally reported binding energies for HIV-1 protease inhibitors. 3D QSAR and computational ADMET study were performed. Pharmacophore fragments of the compound were identified as well as the fragments determining its toxicity and metabolic properties. Based on the analysis of these fragments, the ways to further design promising HIV1-protease inhibitors were proposed.