Indolactam-V Is Involved in the CH/π Interaction with Pro-11 of the PKCδ C1B Domain:  Application for the Structural Optimization of the PKCδ Ligand

Nakagawa, Yu; Irie, Kazuhiro; Yanagita, Ryo C.; Ohigashi, Hajime; Tsuda, Katsutoshi

doi:10.1021/ja050447d

Cited by 42 publications

(38 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the lower Ki value of ILV (34) compared to compound 38 (80 and 1700 nM, respectively) was explained by CH/π interactions between the indole ring in ILV and Pro241 in PKCδ [135,140].…”

Section: Structure-activity Studiesmentioning

confidence: 94%

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Gennäs

Talman²,

Yli‐Kauhaluoma³

et al. 2011

CTMC

View full text Add to dashboard Cite

Protein kinase C (PKC) comprises a family of ten isoforms that play roles in diverse cellular processes such as proliferation, apoptosis and differentiation. PKC isoforms respond to Gprotein coupled receptor-and receptor tyrosine kinase-signaling via binding the second messenger diacylglycerol with C1 domains. Aberrant signaling through PKC isoforms and other C1 domain-containing proteins has been implicated in several pathological disorders.Drug discovery concerning C1 domains has exploited natural products and rationally designed compounds. Currently, molecules from several classes of C1 domain-binding compounds are in clinical trials; however, still more have the potential to enter the drug development pipeline. This review gives a summary of the recent developments in C1 domain-binding compounds.

show abstract

Section: Structure-activity Studiesmentioning

confidence: 94%

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Gennäs

Talman²,

Yli‐Kauhaluoma³

et al. 2011

CTMC

View full text Add to dashboard Cite

show abstract

“…52 (−)-Indolactam V is a broad spectrum agonist of novel and classical PKCs. 54,55 But the novel PKC isoform Δ is a target of the RA-signaling pathway, providing evidence for an analogous effect of (−)-Indolactam V to that of RA on ESCs. 56,57 On the other hand, neither knock out of classical PKCs 58,59 nor knockout of novel PKCs 60,61 had a negative effect on mouse pancreatic, endocrine development as would be expected if PKC did play a critical role.…”

Section: Role Of Small Molecules During Differentiationmentioning

confidence: 99%

Insulin-producing Surrogate β-cells From Embryonic Stem Cells: Are We There Yet?

et al. 2011

View full text Add to dashboard Cite

Embryonic stem cells (ESCs) harbor the potential to generate every cell type of the body by differentiation. The use of hESCs holds great promise for potential cell replacement therapies for degenerative diseases including diabetes mellitus. The recently discovered induced pluripotent stem cells (iPSCs) exhibit immense potential for regenerative medicine as they allow the generation of autologous cells tailored to the patients' immune system. Research for insulin-producing surrogate cells from ESCs has yielded highly controversial results, because many steps and factors in the differentiation process are currently still unknown. Thus, there is no consensus on common standard protocols. The protocols presently used established the differentiation from pluripotent cells toward pancreatic progenitor cells. However, none of the differentiation protocols reported to date have generated by exclusive in vitro differentiation sufficient numbers of insulin-producing cells meeting all essential criteria of a β-cell. The cells often lack the crucial function of regulated insulin secretion upon glucose stimulation. This review focuses on past and current approaches to the generation of insulin-producing cells from pluripotent sources, such as ESCs and iPSCs, and critically discusses the hurdles to be taken before insulin-secreting surrogate cells derived from these stem cells will be of clinical use in humans.

show abstract

“…An instructive example underlying the importance of the CH··· interaction was reported by Irie and co-workers for the binding of indolactam-V (IL-V) and its analogs to the C1B domain of Protein kinase (PKC) C [44,45]. PKC isozymes are the main receptors of tumor promoters and mutational studies have revealed that Pro11 plays an important role in the binding of IL-V to PKC [46].…”

Section: Examples Of C ··· Interactions In Therapeutically Relevant Pmentioning

confidence: 99%

The Role and Significance of Unconventional Hydrogen Bonds in Small Molecule Recognition by Biological Receptors of Pharmaceutical Relevance

Tóth¹,

Bowers²,

Truong³

et al. 2007

CPD

View full text Add to dashboard Cite

The discovery and optimization of nonbonded interactions, such as van der Waals interactions, hydrogen bonds, salt bridges and the hydrophobic effect, between small molecule ligands and their receptors is one of the main challenges in rational drug discovery. As the theory of molecular interactions advances more evidence accumulates that nonbonded interactions, such as unconventional hydrogen bonds (X-H...Y interactions, where X can be either C, N or O atom and Y can be either an aromatic ring system O or F atom), contribute to ligand recognition by biological receptors. This review provides an overview of unconventional hydrogen bonds between ligands and their receptors of pharmaceutical relevance by dissecting their structure activity relationships and 3D structural elements. Gaining an understanding of the energetic and the structural properties of unconventional hydrogen bonds in ligand-receptor interactions leads us to the elucidation of their practical significance. Ultimately, this enables us to consciously apply these interactions in hit and lead optimization in rational structure based drug design.

show abstract

Indolactam-V Is Involved in the CH/π Interaction with Pro-11 of the PKCδ C1B Domain: Application for the Structural Optimization of the PKCδ Ligand

Cited by 42 publications

References 18 publications

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Insulin-producing Surrogate β-cells From Embryonic Stem Cells: Are We There Yet?

The Role and Significance of Unconventional Hydrogen Bonds in Small Molecule Recognition by Biological Receptors of Pharmaceutical Relevance

Contact Info

Product

Resources

About