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Structure-based design of selective phosphodiesterase 4B inhibitors based on ginger phenolic compounds.
J Biomol Struct Dyn. 2017 Oct; 35(13):2910-2924.JB

Abstract

Phosphodiesterase 4 (PDE4) has been established as a drug target for inflammatory diseases of respiratory tract like asthma and chronic obstructive pulmonary disease. The selective inhibitors of PDE4B, a subtype of PDE4, are devoid of adverse effects like nausea and vomiting commonly associated with non-selective PDE4B inhibitors. This makes the development of PDE4B subtype selective inhibitors a desirable research goal. Thus, in the present study, molecular docking, molecular dynamic simulations and binding free energy were performed to explore potential selective PDE4B inhibitors based on ginger phenolic compounds. The results of docking studies indicate that some of the ginger phenolic compounds demonstrate higher selective PDE4B inhibition than existing selective PDE4B inhibitors. Additionally, 6-gingerol showed the highest PDE4B inhibitory activity as well as selectivity. The comparison of binding mode of PDE4B/6-gingerol and PDE4D/6-gingerol complexes revealed that 6-gingerol formed additional hydrogen bond and hydrophobic interactions with active site and control region 3 (CR3) residues in PDE4B, which were primarily responsible for its PDE4B selectivity. The results of binding free energy demonstrated that electrostatic energy is the primary factor in elucidating the mechanism of PDE4B inhibition by 6-gingerol. Dynamic cross-correlation studies also supported the results of docking and molecular dynamics simulation. Finally, a small library of molecules were designed based on the identified structural features, majority of designed molecules showed higher PDE4B selectivity than 6-gingerol. These results provide important structural features for designing new selective PDE4B inhibitors as anti-inflammatory drugs and promising candidates for synthesis and pre-clinical pharmacological investigations.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Xing M
a Faculty of Pharmaceutical Sciences , UCSI University , No. 1, UCSI Heights, Jalan Menara Gading, Taman Connaught, 56000 Kuala Lumpur , Federal Territory of Kuala Lumpur , Malaysia.
Akowuah GA
a Faculty of Pharmaceutical Sciences , UCSI University , No. 1, UCSI Heights, Jalan Menara Gading, Taman Connaught, 56000 Kuala Lumpur , Federal Territory of Kuala Lumpur , Malaysia.
Gautam V
b Department of Chemistry, Faculty of Science , University of Malaya , 50603 Kuala Lumpur , Federal Territory of Kuala Lumpur , Malaysia.
Gaurav A
a Faculty of Pharmaceutical Sciences , UCSI University , No. 1, UCSI Heights, Jalan Menara Gading, Taman Connaught, 56000 Kuala Lumpur , Federal Territory of Kuala Lumpur , Malaysia.

MeSH

Anti-Inflammatory AgentsCatalytic DomainCatecholsCyclic Nucleotide Phosphodiesterases, Type 4Fatty AlcoholsGingerHydrogen BondingMolecular Docking SimulationMolecular Dynamics SimulationPhenolPhosphodiesterase 4 Inhibitors

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27608741

Citation

Xing, Ming, et al. "Structure-based Design of Selective Phosphodiesterase 4B Inhibitors Based On Ginger Phenolic Compounds." Journal of Biomolecular Structure & Dynamics, vol. 35, no. 13, 2017, pp. 2910-2924.
Xing M, Akowuah GA, Gautam V, et al. Structure-based design of selective phosphodiesterase 4B inhibitors based on ginger phenolic compounds. J Biomol Struct Dyn. 2017;35(13):2910-2924.
Xing, M., Akowuah, G. A., Gautam, V., & Gaurav, A. (2017). Structure-based design of selective phosphodiesterase 4B inhibitors based on ginger phenolic compounds. Journal of Biomolecular Structure & Dynamics, 35(13), 2910-2924. https://doi.org/10.1080/07391102.2016.1234417
Xing M, et al. Structure-based Design of Selective Phosphodiesterase 4B Inhibitors Based On Ginger Phenolic Compounds. J Biomol Struct Dyn. 2017;35(13):2910-2924. PubMed PMID: 27608741.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structure-based design of selective phosphodiesterase 4B inhibitors based on ginger phenolic compounds. AU - Xing,Ming, AU - Akowuah,Gabriel Akyirem, AU - Gautam,Vertika, AU - Gaurav,Anand, Y1 - 2016/09/27/ PY - 2016/9/10/pubmed PY - 2018/5/17/medline PY - 2016/9/10/entrez KW - Phosphodiesterase 4B KW - anti-inflammatory KW - docking KW - gingerol KW - molecular dynamics SP - 2910 EP - 2924 JF - Journal of biomolecular structure & dynamics JO - J Biomol Struct Dyn VL - 35 IS - 13 N2 - Phosphodiesterase 4 (PDE4) has been established as a drug target for inflammatory diseases of respiratory tract like asthma and chronic obstructive pulmonary disease. The selective inhibitors of PDE4B, a subtype of PDE4, are devoid of adverse effects like nausea and vomiting commonly associated with non-selective PDE4B inhibitors. This makes the development of PDE4B subtype selective inhibitors a desirable research goal. Thus, in the present study, molecular docking, molecular dynamic simulations and binding free energy were performed to explore potential selective PDE4B inhibitors based on ginger phenolic compounds. The results of docking studies indicate that some of the ginger phenolic compounds demonstrate higher selective PDE4B inhibition than existing selective PDE4B inhibitors. Additionally, 6-gingerol showed the highest PDE4B inhibitory activity as well as selectivity. The comparison of binding mode of PDE4B/6-gingerol and PDE4D/6-gingerol complexes revealed that 6-gingerol formed additional hydrogen bond and hydrophobic interactions with active site and control region 3 (CR3) residues in PDE4B, which were primarily responsible for its PDE4B selectivity. The results of binding free energy demonstrated that electrostatic energy is the primary factor in elucidating the mechanism of PDE4B inhibition by 6-gingerol. Dynamic cross-correlation studies also supported the results of docking and molecular dynamics simulation. Finally, a small library of molecules were designed based on the identified structural features, majority of designed molecules showed higher PDE4B selectivity than 6-gingerol. These results provide important structural features for designing new selective PDE4B inhibitors as anti-inflammatory drugs and promising candidates for synthesis and pre-clinical pharmacological investigations. SN - 1538-0254 UR - https://www.unboundmedicine.com/medline/citation/27608741/Structure_based_design_of_selective_phosphodiesterase_4B_inhibitors_based_on_ginger_phenolic_compounds_ DB - PRIME DP - Unbound Medicine ER -