![]() ![]() The π–π stacking interaction that was formed between the aromatic ring and the imidazole group of HIS499 in the first coordination sphere of iron was preserved for 31% of the simulation time, while the same type of interaction observed between the second phenyl ring and the indole group of TRP500 was for 55% of the simulation time. Moreover, the key interactions that are formed between the molecule and the residues of the cavity were preserved from the docking studies throughout the whole simulation. In particular, the first phenyl ring is oriented toward HIS499, while the second is toward TRP500. The conformations that the inhibitor adopts inside the cavity do not present significant changes in comparison to the initial docking pose (reference pose), and the orientation of the molecule remains similar to the first MD snapshot. Furthermore, they both strongly inhibit lipid peroxidation, namely, 98% for KKII5 and 94% for DKI5.Īccording to the MD studies, KKII5 remains bound to the active site of the enzyme during the production time. The two very potent LOX-1 inhibitors exerted IC 50 19 μΜ ( KKII5) and 22.5 μΜ ( DKI5). This is related to the stronger binding interaction of KKII5 relative to that of DK15 to LOX-1. Thus, KKII5 enhanced the ability of the active center to receive electrons compared to DKI5. The results showed a significantly smaller energy attachment of 2.8 eV with KKII5 binding in comparison to DKI5. The redox potential of the active center of LOX-1 with the binding molecules was calculated via DFT methodology. ![]() ADMET calculations showed that the two molecules lack major toxicities and could serve as possible drug leads. The strongest binding energy, −9.60 kcal/mol, was observed for dihydropyrimidinethione KKII5 in the active site of LOX-1. These in silico experiments and DFT calculations indicated favorable binding for the enzyme under study. Additionally, docking and molecular dynamics simulations were performed to discover their ability to bind and remain stabile in the active site of the LOX-1 enzyme. The obtained DFT lowest energy conformers were in agreement with the NOE correlations observed in the 2D-NOESY spectra. Specifically, the structure assignment and conformational analysis were achieved by applying homonuclear and heteronuclear 2D nuclear magnetic resonance (NMR) spectroscopy (2D-COSY, 2D-NOESY, 2D-HSQC, and 2D-HMBC) and density functional theory (DFT). Their structure, binding in the active site of the LOX-1 enzyme, and their toxicity are studied via joint experimental and computational methodologies. KKII5 and DKI5 are synthesized in high yield of up to 97%. The potential of the 4,6-diphenyl-3,4-dihydropyrimidine-2(1 H)-thione (abbreviated as KKII5) and ( E)- N′-benzylidenehydrazinecarbothiohydrazide (abbreviated as DKI5) compounds as possible drug leads is investigated. ![]()
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