Modification of MM force fields around heme-Fe in the CYP-ligand complex and ab initio FMO calculations for the complex.

Cytochrome P450 (CYP) enzymes play essential roles in the synthesis and metabolic activation of physiologically active substances. CYP has a prosthetic heme (iron protoporphyrin IX) in its active center, where Fe ion (heme-Fe) is deeply involved in enzymatic reactions of CYP. To precisely describe the structure and electronic states around heme-Fe, we modified the force fields (FFs) around heme-Fe in molecular mechanics (MM) simulations and conducted ab initio fragment molecular orbital (FMO) calculations for the CYP-ligand complex.

In Silico Design of Natural Inhibitors of ApoE4 from the Plant : Molecular Docking and Ab Initio Fragment Molecular Orbital Calculations.

Alzheimer's disease (AD) is a neurological disease, and its signs and symptoms appear slowly over time. Although current Alzheimer's disease treatments can alleviate symptoms, they cannot prevent the disease from progressing. To accurately diagnose and treat Alzheimer's disease, it is therefore necessary to establish effective methods for diagnosis.

Elucidating specific interactions for designing novel pyrrolamide derivatives as potential GyrB inhibitors based on fragment molecular orbital calculations.

Tuberculosis (TB), the second leading infectious killer, causes serious public health problems worldwide. To develop novel anti-TB agents, many biochemical studies have targeted the subunit B of DNA gyrase (GyrB), which captures a second DNA segment and responses for ATP hydrolysis. Here, we investigated specific interactions between GyrB residues and existing pyrrolamide derivatives at an electronic level using fragment molecular orbital (FMO) calculations and designed potent inhibitors against GyrB.

Proposal of novel ApoE4 inhibitors from the natural spice Cinnamon for the treatment of Alzheimer's disease: Ab initio molecular simulations.

Alzheimer's disease (AD), one of the most common neurodegenerative diseases, is a major factor contributing to cognitive impairment in older adults. Current therapeutic treatments can only relieve the symptoms of AD, but they cannot stop the progression of the disease because it takes a long time for clinical symptoms to manifest. Therefore, it is essential to develop effective diagnostic strategies for early detection and treatment of AD.

Structure-based drug design of novel M. tuberculosis InhA inhibitors based on fragment molecular orbital calculations.

2-trans enoyl-acyl carrier protein reductase (InhA) is a promising target for developing novel chemotherapy agents for tuberculosis, and their inhibitory effects on InhA activity were widely investigated by the physicochemical experiments. However, the reason for the wide range of their inhibitory effects induced by similar agents was not explained by only the difference in their chemical structures. In our previous molecular simulations, a series of heteroaryl benzamide derivatives were selected as candidate inhibitors against InhA, and their binding properties with InhA were investigated to propose novel derivatives with higher binding affinity to InhA.

Natural inhibitors for severe acute respiratory syndrome coronavirus 2 main protease from , , and : molecular docking and ab initio fragment molecular orbital calculations.

Unlabelled: The novel coronavirus 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide, and new drug treatments for COVID-19 are urgently required. To find the potential inhibitors against the main protease (Mpro) of SARS-CoV-2, we investigated the inhibitory potential of naturally occurring compounds from the plants , , and , using molecular docking, classical molecular mechanics optimizations, and ab initio fragment molecular orbital (FMO) calculations. Of the 35 compounds that we simulated, feralolide from exhibited the highest binding affinity against Mpro.

Water molecule-mediated selective inhibition of bacterial zinc metalloproteinases by non-hydroxamate compounds: Ab initio molecular simulations.

UDP-3-O-acyl-N acetylglucosamine deacetylase (LpxC), Zn metalloenzyme for Gram-negative bacteria is an attractive target for developing novel therapeutic agents. Since LpxC has the similar binding pocket as the human matrix metalloproteinases (MMPs), LpxC inhibitors might also inhibit MMP functions producing side effects in human bodies. Here, we investigated specific interactions between LpxC/MMP and their inhibitors using ab initio molecular simulations to elucidate the reason of selective inhibition for LpxC by non-hydroxamate compounds.

Specific interactions between the alkaline protease of P. aeruginosa and its natural peptide inhibitor: ab initio molecular simulations.

Alkaline protease aeruginolysin (APR) is an important virulence factor in the evasion of the immune system by Pseudomonas aeruginosa (P. aeruginosa). The P.

Proposal of selective inhibitor for bacterial zinc metalloprotease: Molecular mechanics and ab initio molecular orbital calculations.

The zinc metalloprotease pseudolysin (PLN) secreted from Pseudomonas aeruginosa degrades extracellular proteins to produce bacterial nutrition, and various types of PLN inhibitors have been developed to suppress the bacterial growth. However, as the structure of the ligand-binding pocket of PLN has large similarities to those of human matrix metalloproteinases (MMPs) and other human zinc metalloprotease, there is a risk that PLN inhibitors also inhibit human zinc proteases. In this study, we propose a novel agent that may bind stronger to PLN than to MMPs.

Single-molecule junction spontaneously restored by DNA zipper.

The electrical properties of DNA have been extensively investigated within the field of molecular electronics. Previous studies on this topic primarily focused on the transport phenomena in the static structure at thermodynamic equilibria. Consequently, the properties of higher-order structures of DNA and their structural changes associated with the design of single-molecule electronic devices have not been fully studied so far.

Proposal of novel natural inhibitors of severe acute respiratory syndrome coronavirus 2 main protease: Molecular docking and ab initio fragment molecular orbital calculations.

This paper proposes natural drug candidate compounds for the treatment of coronavirus disease 2019 (COVID-19). We investigated the binding properties between the compounds in the Moringa oleifera plant and the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 using molecular docking and ab initio fragment molecular orbital calculations. Among the 12 compounds, niaziminin was found to bind the strongest to Mpro.

Proposal of novel potent inhibitors against androgen receptor based on ab initio molecular orbital calculations.

The androgen receptor (AR), a family of nuclear receptor proteins, stimulates the transcription of androgen-responsive genes. As its abnormal activation can cause the progression of prostate cancer, numerous types of ligands for AR have been developed as promising antagonists for the treatment of prostate cancer. We previously investigated the specific interactions between AR and nine types of existing non-steroidal ligands, using molecular simulations based on molecular mechanics and ab initio fragment molecular orbital methods.

FMODB: The World's First Database of Quantum Mechanical Calculations for Biomacromolecules Based on the Fragment Molecular Orbital Method.

We developed the world's first web-based public database for the storage, management, and sharing of fragment molecular orbital (FMO) calculation data sets describing the complex interactions between biomacromolecules, named FMO Database (https://drugdesign.riken.jp/FMODB/).

Proposal of novel inhibitors for vitamin-D receptor: Molecular docking, molecular mechanics and ab initio molecular orbital simulations.

The specific binding of active vitamin-D to the vitamin-D receptor (VDR) is closely related to the onset of immunological diseases. To inhibit the binding, various compounds have been developed as potent inhibitors against VDR. Among them, a compound NS-54c, which was developed based on the first VDR antagonist TEI-9647 (25-dehydro-1α-hydroxyvitamin D-26,23-lactone), was revealed to posse almost 1000-fold improved antagonistic activity over the original TEI-9647.

Proposal of Potent Inhibitors for a Bacterial Cell Division Protein FtsZ: Molecular Simulations Based on Molecular Docking and ab Initio Molecular Orbital Calculations.

The inhibition of a bacterial cell division protein, filamentous temperature-sensitive Z (FtsZ), prevents the reproduction of . To propose potent inhibitors of FtsZ, the binding properties of FtsZ with various derivatives of Zantrin ZZ3 were investigated at an electronic level, using molecular simulations. We here employed protein-ligand docking, classical molecular mechanics (MM) optimizations, and ab initio fragment molecular orbital (FMO) calculations.

Structural change of retinoic-acid receptor-related orphan receptor induced by binding of inverse-agonist: Molecular dynamics and molecular orbital simulations.

To elucidate structural changes in the retinoic acid receptor-related orphan receptor gamma (RORγt) induced by the binding of an agonist or an inverse agonist, we conducted molecular dynamics (MD) simulations in explicit water. In addition, fragment molecular orbital calculations were carried out for certain characteristic structures obtained from the MD simulations to reveal important interactions between the amino acid residues of RORγt, and to distinguish the different effects in the binding of an agonist and an inverse agonist on the structure of RORγt. The results elucidate that the hydrogen bond between His479 of helix11 (H11) and Tyr502 of helix12 (H12) is important to keep the H12 conformation in the agonist-bound RORγt.

Specific interactions between tau protein and curcumin derivatives: Molecular docking and ab initio molecular orbital simulations.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the world, and there is currently no potent medicine for the treatment of ADs. Curcumin, a primary chemical contained in the ancient Indian herb known as turmeric, has been extensively studied and shown to be effective in inhibiting the aggregations of amyloid-β and tau proteins, both of which are observed in the brains of AD patients. In the present study, we focused on the tau protein and investigated its specific interactions with curcumin derivatives, using molecular simulations based on molecular docking, molecular mechanics and ab initio fragment molecular orbital calculations.

Protonation states of central amino acids in a zinc metalloprotease complexed with inhibitor: Molecular mechanics optimizations and ab initio molecular orbital calculations.

The zinc-metalloprotease pseudolysin (PLN) secreted from bacteria degrades extracellular proteins to produce bacterial nutrition. Since PLN has a Zn ion at the inhibitor-binding site, the interactions between Zn and PLN residues as well as inhibitor can be significantly changed depending on the protonation states of PLN residues at the inhibitor-binding site. To determine stable protonation states of these residues, we here considered different protonation states for Glu and His residues located around Zn and investigated the electronic states of the PLN + inhibitor complex, using ab initio molecular simulations.

Design of galardine analogs as putative psudolysin inhibitors based on fragment molecular orbital calculations.

Pseudolysin (PLN) is a metalloproteinase secreted from bacteria that degrades extracellular proteins to produce bacterial nutrition. It is thus expected that inhibitors against PLN can suppress the growth of bacteria and their pandemic spread. In addition, since these inhibitors do not attack to bacteria directly, there is a reduced risk for producing drug-resistant bacteria.

Change in binding states between catabolite activating protein and DNA induced by ligand-binding: molecular dynamics and ab initio fragment molecular orbital calculations.

The transcription mechanism of genetic information from DNA to RNA is efficiently controlled by regulatory proteins, such as catabolite activator protein (CAP), and their ligands. When cyclic AMP (cAMP) binds to CAP, the complex forms a dimer and binds specifically to DNA to activate the transcription mechanism. On the other hand, when cyclic GMP (cGMP) binds to CAP, the complex has no marked effect on the mechanism.

Specific interactions between 2-trans enoyl-acyl carrier protein reductase and its ligand: Protein-ligand docking and ab initio fragment molecular orbital calculations.

2-trans enoyl-acyl carrier protein reductase (InhA) has been identified as a promising target for the development of novel chemotherapy for tuberculosis. In the present study, a series of heteroaryl benzamide derivatives were selected as potent inhibitors against InhA, and their binding properties with InhA were investigated at atomic and electronic levels by ab initio molecular simulations based on protein-ligand docking, classical molecular mechanics optimizations and ab initio fragment molecular orbital (FMO) calculations. The results evaluated by FMO highlight some key interactions between InhA and the derivatives, indicating that the most potent derivative has strong hydrogen bonds with the Met98 side chain of InhA and strong electrostatic interactions with the nicotinamide adenine dinucleotide cofactor.

Ligand chirality can affect histidine protonation of vitamin-D receptor: ab initio molecular orbital calculations in water.

Vitamin D is recognized to play important roles in the onset of immunological diseases as well as the regulation of the amount of Ca in the blood. Since these physiological actions caused by active vitamin D are triggered by the specific interaction between the vitamin D receptor (VDR) and active vitamin D, many types of compounds have been developed as potent ligands against VDR. It was found that the binding affinity between VDR and its ligand depends significantly on the chirality of the ligand.

Proposal of potent inhibitors for vitamin-D receptor based on ab initio fragment molecular orbital calculations.

Vitamin D plays an important role in the regulation of the calcium and phosphorus metabolism as well as in bone formation. These physiological actions caused by vitamin D are triggered by the specific binding of vitamin D to its receptor (VDR). Here we investigated the specific interactions and binding affinities between VDR and vitamin D derivatives, using ab initio fragment molecular orbital (FMO) calculations.

A novel peptide blocking cancer cell invasion by structure-based drug design.

The receptor for the urokinase-type plasminogen activator (uPA), uPAR, facilitates tumor cell invasion and metastasis by focusing on several ligands, including uPA, integrins and vitronectin. With computational prediction algorithms and structure-based drug design, we identified peptides containing the Gly-Lys-Gly-Glu-Gly-Glu-Gly-Lys-Gly sequence (peptide H1), which strongly interacts with uPAR. The aim of the present study was to investigate the effect of allosteric inhibition at the uPAR interface using a novel synthetic peptide and its function on ovarian cancer cell invasion.

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.