title: Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation.
abstract: Transient receptor potential vanilloid type 1 (TRPV1), a heat-sensitive calcium channel protein, contributes to inflammation as well as to acute and persistent pain. Since TRPV1 occupies a central position in pathways of neuronal inflammatory signaling, it represents a highly attractive potential therapeutic target for neuroinflammation. In the present work, we have in silico identified a series of diarylurea analogues for hTRPV1, of which 11 compounds showed activity in the nanomolar to micromolar range as validated by in vitro biological assays. Then, we utilized molecular docking to explore the detailed interactions between TRPV1 and the compounds to understand the contributions of the different substituent groups. Tyr511, Leu518, Leu547, Thr550, Asn551, Arg557, and Leu670 were important for the recognition of the small molecules by TRPV1. A hydrophobic group in R2 or a polar/hydrophilic group in R1 contributed significantly to the activities of the antagonists at TRPV1. In addition, the subtle different binding pose of meta-chloro in place of para-fluoro in the R2 group converted antagonism into partial agonism, as was predicted by our short-term molecular dynamics (MD) simulation and validated by bioassay. Importantly, compound 15, one of our best TRPV1 inhibitors, also showed potential binding affinity (1.39 μM) at cannabinoid receptor 2 (CB2), which is another attractive target for immuno-inflammation diseases. Furthermore, compound 1 and its diarylurea analogues were predicted to target the C-X-C chemokine receptor 2 (CXCR2), although bioassay validation of CXCR2 with these compounds still needs to be performed. This prediction from the modeling is of interest, since CXCR2 is also a potential therapeutic target for chronic inflammatory diseases. Our findings provide novel strategies to develop a small molecule inhibitor to simultaneously target two or more inflammation-related proteins for the treatment of a wide range of inflammatory disorders including neuroinflammation and neurodegenerative diseases with potential synergistic effect.
authors.affiliation: Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, 20892, USA.
authors.forename: Larry V
authors.initials: LV
authors.lastname: Pearce
authors.affiliation: Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Changrui
authors.initials: C
authors.lastname: Xing
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, 20892, USA.
authors.forename: Brienna K A
authors.initials: BK
authors.lastname: Herold
authors.affiliation: Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Shifan
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Ziheng
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, 20892, USA.
authors.forename: Noe A
authors.initials: NA
authors.lastname: Turcios
authors.affiliation: Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.|Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, 20892, USA.
authors.forename: Anna K
authors.initials: AK
authors.lastname: McCall
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, 20892, USA. blumberp@dc37a.nci.nih.gov.|Laboratory of Cancer Biology and Genetics, National Institutes of Health, Building 37, Room 4048B, 37 Convent Drive MSC 4255, Bethesda, Maryland, 20892-4255, USA. blumberp@dc37a.nci.nih.gov.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.affiliation: Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. xix15@pitt.edu.|NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. xix15@pitt.edu.|Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. xix15@pitt.edu.|Departments of Computational Biology and of Structural Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, USA. xix15@pitt.edu.
authors.forename: Xiang-Qun
authors.initials: XQ
authors.lastname: Xie
mesh_terms: D006801:Humans; D007249:Inflammation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010146:Pain / Q000188:drug therapy; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D050916:TRPV Cation Channels
keywords: TRPV1; multi-targets; neuroinflammation; pain; synergistic effect