Aggregation properties of a therapeutic peptide for rheumatoid arthritis: A spectroscopic and molecular dynamics study

Introduction: Rheumatoid Arthritis [RA] is an autoimmune disease that can cause chronic inflammation of the joints. Human DiHydroOrotate DeHydrogenase [DHODH] is a clinically validated drug target for the treatment of Rheumatoid Arthritis. DHODH inhibition results in beneficial immunosuppressant and anti-proliferative effects. Materials and Methods: Leflunomide [LEF] and Brequinar Sodium [BREQ], drugs used in the treatment of RA, suppresses the immune cells responsible for inflammation but has several side-effects, most predominant being symptomatic liver damage and toxicity. An existing scaffold based on structural analogies with LEF and BREQ was used to screen out potent inhibitors of DHODH, in ZINC Database using 2D binary fingerprint. 10 structures similar to the scaffold were shortlisted due to their Tanimoto similarity coefficient. Selected structures were docked using the tools AutoDock, Ligand fit and iGEMDOCK with target human DHODH. High scoring compounds having similar interactions as that of scaffold were checked to evaluate their Drug-Likeliness. Results: The five shortlisted compounds were then subjected to Molecular Dynamics Simulation studies for 50ns using GROMACS. Measures of structural similarity based on 2D Fingerprint Screening and Molecular Dynamics Simulation studies can suggest good leads for drug designing. The novelty of this study is that the workflow used here yields the same results that are at par with the experimental data. Conclusion: This suggests the use of the 2D fingerprint similarity search in various databases, followed by multiple docking algorithms and dynamics as a workflow that will lead to finding novel compounds that a structurally and functionally similar to LEF and BREQ.

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Predict the Strong Binding Ability Polypeptide of Human α-Enolase with the HLA-DRB1 * 0401

Applied Mechanics and Materials ◽

10.4028/www.scientific.net/amm.380-384.4353 ◽

2013 ◽

Vol 380-384 ◽

pp. 4353-4358

Author(s):

Rui Jie ◽

Quan Zhou ◽

Jin Song Wang ◽

Yun He Liang ◽

Ting Ting Liao ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Molecular Dynamics ◽

Mhc Class Ii ◽

Structural Model ◽

Three Dimensional ◽

Prediction Method ◽

T Cell Epitopes ◽

Binding Ability ◽

Strong Binding ◽

Chain Conformations

Human α-enolase (ENO1), an evolutionarily conserved and multifunctional protein, is a target self-antigen of rheumatoid arthritis (RA). Rheumatoid arthritis (RA) is genetically associated with MHC class II molecules, such as DRB1*0101, DRB1*0401 and DRB1*0404 allele. Among these DRB1 alleles, DRB1*0401 show the most correlation with RA. However, strong binding ability polypeptide of ENO1 with HLA-DRB1*0401 is still largely unknown. In this study, we used NetMHCII prediction method to predict the strong binding ability polypeptide with HLA-DRB1*0401. Among the 434 predicted fragment peptide, ENO1129-141: PLYRHIADLAGNS showed strong binding with HLA-DR4 and peptide ENO1281-293 KSFIKDYPVVSIE is the second candidate peptide. Based on these result, we choosed EON1129-141 and EON1281-293 polypeptides to do the molecular modeling, and used the molecular dynamics to optimize the three-dimensional structural model. The molecular dynamics results showed that ENO1129-141: PLYRHIADLAGNS and ENO1281-293: KSFIKDYPVVSIE have strong binding ability with HLA-DR4* 0401. In the shared epitope, both ENO1129-141and ENO1281-293 have the very near distance 3.15Å and 3.10Å with K71 of the β1 chain. The main-chain conformations of ENO1129-141 sit more deeply with β1 chain. All together, results indicated that ENO1129-141 and ENO1281-293 bind strong with HLA-DR4 and would be potential T cell epitopes of human α-enolase that induced RA.

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Identification of Phosphoinositide-3 Kinases Delta and Gamma Dual Inhibitors Based on the p110δ/γ Crystal Structure

Letters in Drug Design & Discovery ◽

10.2174/1570180816666190730163431 ◽

2020 ◽

Vol 17 (6) ◽

pp. 772-786

Author(s):

Wen-Qing Jia ◽

Xiao-Yan Feng ◽

Ya-Ya Liu ◽

Zhen-Zhen Han ◽

Zhi Jing ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Crystal Structure ◽

Molecular Dynamics ◽

Virtual Screening ◽

Drug Target ◽

Md Simulations ◽

Biological Processes ◽

Lead Compound ◽

Dual Inhibitors ◽

Low Toxicity

Background: Phosphoinositide-3 kinases (PI3Ks) are key signaling molecules that affect a diverse array of biological processes in cells, including proliferation, differentiation, survival, and metabolism. The abnormal activity of PI3K signals is closely related to the occurrence of many diseases, which has become a very promising drug target, especially for the treatment of cancer. PI3Kδ/γ inhibitors can reduce toxicity concerns for chronic indications such as asthma and rheumatoid arthritis compared with pan PI3Ks inhibitors. Methods: With the aim of finding more effective PI3Kδ/γ dual inhibitors, virtual screening, ADMET prediction Molecular Dynamics (MD) simulations and MM-GBSA were executed based on the known p110δ/γ crystal structure. Compound ZINC28564067 with high docking score and low toxicity was obtained. Results: By MD simulations and MM-GBSA, we could observe that ZINC28564067 had more favorable conformation binding to the PI3Kδ/γ than the original ligands. Conclusion: The results provided a rapid approach for the discovery of novel PI3Kδ/γ dual inhibitors which might be a potential anti-tumor lead compound.

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