Computational Investigation of a Series of Small Molecules as Potential Compounds for Lysyl Hydroxylase-2 (LH2) Inhibition

The catalytic function of lysyl hydroxylase-2 (LH2), a member of the Fe(II)/αKG-dependent oxygenase superfamily, is to catalyze the hydroxylation of lysine to hydroxylysine in collagen, resulting in stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs). Reports show that high amounts of LH2 lead to the accumulation of HLCCs, causing fibrosis and specific types of cancer metastasis. Some members of the Fe(II)/αKG-dependent family have also been reported to have intramolecular

Polarizable ab initio QM/MM Study of the Reaction Mechanism of N-tert-Butyloxycarbonylation of Aniline in [EMIm][BF4]

N-t e r t-butoxycarbonylation of amines in solution (water, organic solvents, or ionic liquids) is a common reaction for the preparation of drug molecules. To understand the reaction mechanism and the role of the solvent, quantum mechanical/molecular mechanical simulations using a polarizable multipolar force field with long–range electrostatic corrections were used to optimize the minimum energy paths (MEPs) associated with various possible reaction mechanisms employing the nudged elastic band (NEB) and the quadratic string method (QSM). The calculated reaction energies and energy barriers were compared with the corresponding gas-phase and dichloromethane results. Complementary Electron Localization Function (ELF)/NCI analyses provide insights on the critical structures along the MEP. The calculated results suggest the most likely path involves a sequential mechanism with the rate–limiting step corresponding to the nucleophilic attack of the aniline, followed by proton transfer and the release of CO 2 without the direct involvement of imidazolium cations as catalysts

Polarizable <i>ab initio</i> QM/MM Study of the Reaction Mechanism of <i>N</i>-<i>tert</i>-Butyloxycarbonylation of Aniline in [EMIm][BF₄]

N-t e r t-butoxycarbonylation of amines in solution (water, organic solvents, or ionic liquids) is a common reaction for the preparation of drug molecules. To understand the reaction mechanism and the role of the solvent, quantum mechanical/molecular mechanical simulations using a polarizable multipolar force field with long&#8315;range electrostatic corrections were used to optimize the minimum energy paths (MEPs) associated with various possible reaction mechanisms employing the nudged elastic band (NEB) and the quadratic string method (QSM). The calculated reaction energies and energy barriers were compared with the corresponding gas-phase and dichloromethane results. Complementary Electron Localization Function (ELF)/NCI analyses provide insights on the critical structures along the MEP. The calculated results suggest the most likely path involves a sequential mechanism with the rate&#8315;limiting step corresponding to the nucleophilic attack of the aniline, followed by proton transfer and the release of CO 2 without the direct involvement of imidazolium cations as catalysts

Current Status of AMOEBA–IL: A Multipolar/Polarizable Force Field for Ionic Liquids

Computational simulations of ionic liquid solutions have become a useful tool to investigate various physical, chemical and catalytic properties of systems involving these solvents. Classical molecular dynamics and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations of IL systems have provided significant insights at the atomic level. Here, we present a review of the development and application of the multipolar and polarizable force field AMOEBA for ionic liquid systems, termed AMOEBA&ndash;IL. The parametrization approach for AMOEBA&ndash;IL relies on the reproduction of total quantum mechanical (QM) intermolecular interaction energies and QM energy decomposition analysis. This approach has been used to develop parameters for imidazolium&ndash; and pyrrolidinium&ndash;based ILs coupled with various inorganic anions. AMOEBA&ndash;IL has been used to investigate and predict the properties of a variety of systems including neat ILs and IL mixtures, water exchange reactions on lanthanide ions in IL mixtures, IL&ndash;based liquid&ndash;liquid extraction, and effects of ILs on an aniline protection reaction

1,3-diketone analogs as selective lysyl hydroxylase 2 (LH2) antagonists

Lysyl hydroxylase 2 (LH2), an Fe(II) and α-ketoglutarate (αKG, also called 2-oxoglutarate, or 2OG)-dependent oxygenase, is an endoplasmic reticulum-resident enzyme that hydroxylates telopeptidyl lysine residues on fibrillar collagen molecules. It leads to the formation of hydroxylysine aldehyde-derived collagen cross-links (HLCCs), which are more stable than lysine aldehyde-derived collagen cross-links (LCCs) generated devoid of LH2. It has been reported that LH2 enhances lung cancer metastatic and invasive proclivity and modulates the types of collagen cross-links (HLCC-to-LCC) in the tumor stroma. Herein, we prepared a series of 1,3-diketone analogs 1–18 and identified 12 and 13 that inhibit the LH2-driven hydroxylation of a collagen peptide substrate with IC50 approximately 300 nM and 500 nM, respectively. 12 and 13 demonstrate a 9-fold selectivity for LH2 over LH1 and LH3. Quantum Mechanics/Molecular Mechanics (QM/MM) modeling indicates that in addition to the relatively stronger interactions between compounds 12 and 13 with the active site, the selectivity stems from non-covalent interactions like hydrogen bonding between the morpholine/piperazine rings with LH2-specific Arg661, where the corresponding residue in LH1 and LH3 is Pro. Migration assays in the 344SQ lung adenocarcinoma cell line reveal that 13 shows anti-migration activity

Computational Investigation of a Series of Small Molecules as Lead Compounds for Lysyl hydroxylase-2 (LH2) Inhibition

The catalytic function of Lysyl hydroxylase-2 (LH2), a member of the Fe(II)/αKG-dependent oxygenase superfamily, is to catalyze the hydroxylation of lysine to hydroxylysine in collagen, resulting in stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs). Reports show that high amounts of LH2 lead to the accumulation of HLCCs, causing fibrosis and specific types of cancer metastasis. Some members of the Fe(II)/αKG-dependent family have also been reported to have intramolecular O2 tunnels, which aid in transporting one of the required co-substrates into the active site. While LH2 can be a promising target to combat these diseases, efficacious inhibitors are still lacking. We have used computational simulations to investigate a series of forty-four small molecules as lead compounds for LH2 inhibition. Tunneling analyses indicate the existence of several intra-molecular tunnels. The lengths of the calculated O2-transporting tunnels in holoenzymes are relatively longer than the apoenzyme suggesting that the ligands may affect the enzyme\u27s structure and possibly block (at least partially) the tunnels. The sequence alignment analysis between LH enzymes from different organisms shows that all the amino acid residues with the highest occurrence rate in the oxygen tunnels are conserved. Our results suggest that the enolate form of diketone compounds establishes stronger interactions with the Fe(II) in the active site. Branching the enolate compounds with functional groups such as phenyl and pyridinyl enhances the interaction with various residues around the active site. Our results provide information about possible leads for further LH2 inhibition design and development