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 immune-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.

PD-1-Targeted Discovery of Peptide Inhibitors by Virtual Screening, Molecular Dynamics Simulation, and Surface Plasmon Resonance

“…The docking program Surflex-Dock GeomX (SFXC) in SYBYL-X 1.3 was utilized to carry out the virtual screening and construction of PD-1-peptide complex in which the docking scores are expressed in −log 10 (K d ) [26]. The main protocols or parameters of docking are listed as follows [27,28,29,30,31]: (a) The “number of starting conformations per ligand” was set to 10, and the “number of max conformations per fragment” was set to 20; (b) the “maximum number of rotatable bonds per molecule” was set to 100; (c) flags were turned on for “pre-dock minimization”, “post-dock minimization”, “molecule fragmentation”, and “soft grid treatment”; (d) “activate spin alignment method with density of search” was set to 9.0; and (e) the “number of spins per alignment” was set to 12.…”

TRPV1: A Target for Rational Drug Design

“…Building on their initial screen Feng et al [ 155 ] further investigated diaryl molecules and screened a library of diarylurea compounds. The rationale for the choice of this class of molecules is the observation, coming from the previous computational studies, of the crucial energetic role played by the interaction between the capsaicin amide group and the side chain of Thr550.…”

Heat activation mechanism of TRPV1: New insights from molecular dynamics simulation

“…In other simulation studies, the conformational changes induced by PI(4,5)P 2 binding were investigated [71], and the binding sites of general anesthetics were identified [72]. In addition, Feng et al carried out MD simulations of human TRPV1 bound with agonist/antagonist to probe the ligand-binding-induced conformational changes and validate their homology model of human TRPV1 [73,74]. To elucidate the TRPV1 heat activation, one MD study simulated the transmembrane domain of TRPV1 at different temperatures, which observed transient partial opening of the channel [75].…”