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

Suzuki, Shusuke; Nakamura, Toshiya; Saito, Ryosuke; Terauchi, Yuta; Kawai, Kentaro; Takimoto‐Kamimura, Midori; Kurita, Noriyuki

doi:10.1016/j.csbj.2020.06.034

Cited by 6 publications

(4 citation statements)

References 30 publications

(41 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the event, adding a chlorine atom to compound 3 in the para position resulted in compound 4 , which inhibited IL-17 secretion from hPBMCs with a half-maximal inhibitory concentration (IC 50 ) of 70.7 nM. Similar dramatic shifts in activity have been described by other researchers, and a detailed molecular dynamics study of these observation has recently been reported . Further optimization of the scaffold is described below.…”

Section: Resultssupporting

confidence: 63%

See 1 more Smart Citation

Defining Target Engagement Required for Efficacy In Vivo at the Retinoic Acid Receptor-Related Orphan Receptor C2 (RORγt)

et al. 2021

View full text Add to dashboard Cite

The Th17 pathway has been implicated in autoimmune diseases. The retinoic acid receptor-related orphan receptor C2 (RORγt) is a master regulator of Th17 cells and controls the expression of IL-17A. RORγt is expressed primarily in IL-17Aproducing lymphoid cells. Here we describe a virtual screen of the ligand-binding pocket and subsequent screen in a binding assay that identified the 1-benzyl-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3c]pyran]-2′-carboxamide scaffold as a starting point for optimization of binding affinity and functional activity guided by structure-based design. Compound 12 demonstrated activity in a mouse PK/PD model and efficacy in an inflammatory arthritis mouse model that were used to define the level and duration of target engagement required for efficacy in vivo. Further optimization to improve ADME and physicochemical properties with guidance from simulations and modeling provided compound 22, which is projected to achieve the level and duration of target engagement required for efficacy in the clinic.

show abstract

Section: Resultssupporting

confidence: 63%

“…Similar dramatic shifts in activity have been described by other researchers, and a detailed molecular dynamics study of these observation has recently been reported. 22 Further optimization of the scaffold is described below.…”

Section: ■ Resultsmentioning

confidence: 99%

Defining Target Engagement Required for Efficacy In Vivo at the Retinoic Acid Receptor-Related Orphan Receptor C2 (RORγt)

et al. 2021

View full text Add to dashboard Cite

show abstract

“…We and newly calculated and collected more than 13 600 FMO calculation data sets ,,− including data sets for 1418 unique PDB entries in collaboration with the FMO Drug Design Consortium (FMODD), which was established for the application of computational science such as FMO calculation to drug discovery. Using these data, we constructed the FMODB, which is a treasure trove of quantitative inter- and intramolecular interaction energies in biomolecular systems that will be useful for a wide range of applications in many life science research fields related to drug discovery and structural biology, including the study of molecular recognition.…”

Section: Introductionmentioning

confidence: 99%

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

Takaya

Watanabe

Nagase

et al. 2021

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

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/). Each entry in the database contains relevant background information on how the data was compiled as well as the total energy of each molecular system and interfragment interaction energy (IFIE) and pair interaction energy decomposition analysis (PIEDA) values. Currently, the database contains more than 13 600 FMO calculation data sets, and a comprehensive search function implemented at the front-end. The procedure for selecting target proteins, preprocessing the experimental structures, construction of the database, and details of the database front-end were described. Then, we demonstrated a use of the FMODB by comparing IFIE value distributions of hydrogen bond, ion-pair, and XH/π interactions obtained by FMO method to those by molecular mechanics approach. From the comparison, the statistical analysis of the data provided standard reference values for the three types of interactions that will be useful for determining whether each interaction in a given system is relatively strong or weak compared to the interactions contained within the data in the FMODB. In the final part, we demonstrate the use of the database to examine the contribution of halogen atoms to the binding affinity between human cathepsin L and its inhibitors. We found that the electrostatic term derived by PIEDA greatly correlated with the binding affinities of the halogen containing cathepsin L inhibitors, indicating the importance of QM calculation for quantitative analysis of halogen interactions. Thus, the FMO calculation data in FMODB will be useful for conducting statistical analyses to drug discovery, for conducting molecular recognition studies in structural biology, and for other studies involving quantum mechanics-based interactions.

show abstract

“…Molecular dynamics (MD) simulations that stand on the static crystal structure can predict atomic-level motion and capture the dynamic information of conformational transitions [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] . As a result of computation and algorithmic promotion, MD simulations have become an important source of complementary information in crystallography and a primary tool for mechanism research [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] .…”

Section: Introductionmentioning

confidence: 99%

Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor

Wang

Liang

et al. 2022

Computational and Structural Biotechnology Journal

View full text Add to dashboard Cite

show abstract

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

Abstract: Graphical abstract Conformational change of His479 side chain in the inverse-agonist-bound RORγt+3SX; (a) at 228 ns and (b) at 230 ns of MD simulations. By the rotation of His side chain, the interactions between His479 and 3SX/Tyr502 are significantly changed.

Cited by 6 publications

References 30 publications

Defining Target Engagement Required for Efficacy In Vivo at the Retinoic Acid Receptor-Related Orphan Receptor C2 (RORγt)

Defining Target Engagement Required for Efficacy In Vivo at the Retinoic Acid Receptor-Related Orphan Receptor C2 (RORγt)

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

Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor

Contact Info

Product

Resources

About