Ryushi Kadoya

Specific interactions between vitamin-D receptor and its ligands: Ab initio molecular orbital calculations in water

Vitamin D is recognized to play important roles not only in the bone metabolism and the regulation of Ca amount in the blood but also in the onset of immunological diseases. These physiological actions caused by vitamin D are triggered by the specific interaction between vitamin D receptor (VDR) and vitamin D. In the present study, we investigated the interactions between VDR and vitamin D derivatives using ab initio molecular simulation, in order to elucidate the reason for the significant difference in their effects on VDR activity. Based on the results simulated, we elucidated which parts of the derivatives and which residues of VDR mainly contribute to the specific binding between VDR and the derivatives at an electronic level. This finding will be helpful for proposing new vitamin D derivatives as a potent modulator or inhibitor against VDR.

Specific interactions between zinc metalloproteinase and its inhibitors: Ab initio fragment molecular orbital calculations

Bacteria secrete the enzyme pseudolysin (PLN) to degrade exocellular proteins, and the produced peptides are used as a nutrient for the bacteria. It is thus expected that inhibition of PLN can suppress bacterial growth. Since such inhibitors do not attack to bacteria directly, the risk of producing drug-resistance bacteria is less. However, endogenous proteinases such as the matrix metalloproteinases (MMPs) have active site similar to that of PLN, and there is a possibility that PLN inhibitors also inhibit the activity of MMPs, resulting in a loss of substrate degradation by these proteinases. Therefore, agents that inhibit the activity of only PLN and not MMPs are required. In the present study, we select two compounds (ARP101 and LM2) and investigate their specific interactions with PLN and MMPs by use of ab initio molecular simulations. Based on the results, we propose several novel compounds as candidates for potent PLN inhibition and investigate their binding properties with PLN, elucidating that the compound, in which a toluene group is introduced into LM2, has larger binding energy with PLN compared with the pristine LM2. Therefore, this compound is suggested to be a potent PLN inhibitor.

Ab initio fragment molecular orbital calculations on the specific interactions between amyloid-β peptides in an in vivo amyloid-β fibril

The accumulation of amyloid-beta (Aβ) fibrils in a brain has been recognized to contribute to the onset of Alzheimers disease (AD). However, the relation between the structure of the aggregate and its toxicity to AD patients remains to be fully elucidated. A recent solid-state NMR analysis for the tissue obtained from the brains of AD patients revealed that the Aβ aggregates have only a single structure with three-fold symmetry. We here investigate the specific interactions between Aβ peptides in the aggregate, using ab initio fragment molecular orbital calculations, to explain why such a unique structure possesses significant stability. The results indicate that the interactions between the Aβ peptides of the stacked Aβ pair are stronger than those between the Aβ peptides of the trimer with three-fold symmetry. Furthermore, it is elucidated that the charged amino-acid residues of Aβ mainly contribute to the strong attractive interactions between the paired Aβ peptides.

Specific interactions between androgen receptor and its ligand: ab initio molecular orbital calculations in water

The Androgen Receptor (AR) is a family of nuclear receptor proteins and a ligand-activated transcription factor. Since its abnormal activation can cause the progression of prostate cancer, numerous types of antagonists against AR have been developed as promising agents for treating prostate cancers. We here investigated the specific interactions between AR and several types of non-steroid agents at an electronic level, using ab initio molecular simulations based on molecular mechanics and ab initio fragment molecular orbital (FMO) methods From the results obtained by FMO, we proposed novel agents as potent ligands against AR and investigated the binding properties between AR and these agents to confirm that some of them can bind more strongly with AR than the existing non-steroid agents and can be strongly effective ligands against AR.

Specific interactions between M. tuberculosis CYP130 and its inhibitors: Molecular simulations using ab initio fragment molecular orbital method

Tuberculosis remains a major global health problem caused by Mycobacterium tuberculosis. Cytochrome P450 enzymes such as CYP130 have an intimate involvement in pathogenesis of tuberculosis. It was demonstrated that azole compounds such as econazole and clotrimazole display inhibitory potential against the latent and multidrug-resistant forms of tuberculosis. Here we investigate the specific interactions between CYP130 and econazole as well as our proposed azole ligands at atomic and electronic levels, using ab initio molecular simulations. The specific interactions between CYP130 and ligand are investigated by ab initio fragment molecular orbital calculations at an electronic level, in order to highlight which residues of CYP130 and which parts of ligand are important for the binding between CYP130 and ligand. Based on the results, we attempt to propose novel potent inhibitors that have a strong binding affinity to CYP130.

Molecular dynamics and ab initio FMO calculations on the effect of water molecules on the interactions between androgen receptor and its ligand and cofactor

To reveal the effect of water molecules on the specific interactions between androgen receptor (AR) and ligand as well as cofactor, we investigated dynamical properties of the complex by the classical molecular dynamics simulations in an explicit water box. Moreover, electronic properties of the complex with and without the water molecules were calculated by ab initio fragment molecular orbital method to find that some of the water molecules contribute significantly to the interactions between AR, ligand and cofactor.

Effect of cofactor-binding on the specific interactions between androgen receptor and its ligand: Ab initio molecular simulations

To elucidate the effect of cofactor YLO on the structure and electronic properties of the androgen receptor (AR) and its ligand (TES) complex, we investigate the change in structure for the AR+TES and the AR+TES+YLO complexes by molecular dynamics simulations in explicit waters. We moreover perform ab initio fragment molecular orbital calculations for the complexes, in order to reveal the change in the specific interactions between AR and TES induced by YLO.

Ab initio molecular simulations based on FMO method for proposing potent inhibitors to reverse transcriptase of HIV

The reverse transcriptase (RT) existing in HIV has been recognized to play an essential role for increasing HIV. It is thus expected that inhibition of the RT activity prevents the increase of HIV. Many types of diarylpyrimidines were synthesized as the inhibitors to RT. Among them, TMC125 and TMC278 were found to play important roles in inhibiting RT activity. In the present study, we picked up some TMC278 derivatives as ligands and investigated the specific interactions between RT and the ligands at atomic and electronic levels, using ab initio fragment molecular orbital (FMO) calculations. First, the derivatives were docked into the ligand-binding pocket of RT using a protein-ligand docking program, and the docked structures were fully optimized in water by a classical molecular mechanics method. Finally, using ab initio FMO calculations, the specific interactions between each amino acid residue of RT and the derivatives were revealed at an electronic level. Based on the FMO results, we proposed some novel inhibitors to RT and demonstrated that one of them binds strongly to RT.

Ab initio molecular simulations on the binding properties between mycobacterial FtsZ and its inhibitor

Filamenting temperature-sensitive mutant Z (FtsZ) is recognized to be essential for performing bacteria cell division. Since the inhibition of activity and polymerization of FtsZ prevents the mycobacteria reproduction, five types of FtsZ inhibitors were defined in the previous experiments, and their effect on FtsZ was investigated. In the present study, we employ these inhibitors as ligands and investigate the specific interactions between FtsZ and these inhibitors at atomic and electronic levels, using ab initio molecular simulations based on protein-ligand docking, classical molecular mechanics optimization and ab initio fragment molecular orbital (FMO) calculations. From the ab initio molecular simulations, some key amino acid residues of FtsZ for the strong binding between FtsZ and ligand are highlighted. Based on the results, we propose a new inhibitor and demonstrate that it has a large binding affinity to FtsZ to be a potent inhibitor to FtsZ.