Design of Inhibitors for Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Enzyme of Leishmania mexicana.

BACKGROUND: Leishmaniosis is a neglected tropical disease and glyceraldehyde 3- phosphate dehydrogenase (GAPDH) is a key enzyme in the design of new drugs to fight this disease. OBJECTIVE: The present study aimed to evaluate potential inhibitors of GAPDH enzyme found in Leishmania mexicana (L. mexicana). METHODS: A search for novel antileishmanial molecules was carried out based on similarities from the pharmacophoric point of view related to the binding site of the crystallographic enzyme using the ZINCPharmer server. The molecules selected in this screening were subjected to molecular docking and molecular dynamics simulations. RESULTS: Consensual analysis of the docking energy values was performed, resulting in the selection of ten compounds. These ligand-receptor complexes were visually inspected in order to analyze the main interactions and subjected to toxicophoric evaluation, culminating in the selection of three compounds, which were subsequently submitted to molecular dynamics simulations. The docking results showed that the selected compounds interacted with GAPDH from L. mexicana, especially by hydrogen bonds with Cys166, Arg249, His194, Thr167, and Thr226. From the results obtained from molecular dynamics, it was observed that one of the loop regions, corresponding to the residues 195-222, can be related to the fitting of the substrate at the binding site, assisting in the positioning and the molecular recognition via residues responsible for the catalytic activity. CONCLUSION: The use of molecular modeling techniques enabled the identification of promising compounds as inhibitors of the GAPDH enzyme from L. mexicana, and the results obtained here can serve as a starting point to design new and more effective compounds than those currently available.

Dual Anti-cancer and Anti-Itch Activity of PD176252 Analogues: Design, Synthesis and Biological Evaluation.

BACKGROUND: Cancer patients treated with targeted anti-cancer drug suffer from itch or pruritus. Itch or pruritus is an unpleasant sensation that brings about a negative impact on quality of life, and serious itch may lead to dose reduction and even discontinuation. Gastrin releasing peptide receptor (GRPR) plays a critical role in itch, inflammation and cancer, and GRPR antagonist has obvious effect on cancer, inflammation and itch. The aim of this paper is to develop a new agent with anti-cancer and anti-itch activity. METHODS: A series of GRPR antagonist PD176252 analogues (3a-3l) were designed and synthesized. Both anticancer and anti-itch activities were evaluated. Anti-cancer activity was evaluated in three human cancer cell lines in vitro, the anti-itch activity in evaluated with Kunming mice by intrathecal injection of chloroquine phosphate as a modeling medium. And the cytotoxicity on normal cells was evaluated. RESULTS: Of the tested compounds, compound 3i showed potently anti-cancer activity to all cancer cell lines tested with IC50 values of 10.5µM (lung), 11.6µM (breast) and 12.8µM (liver) respectively and it also showed significant inhibition of the scratching behavior. Comparing with PD17625, compound 3i and 3g gave better inhibition activities against all cancer cell lines, compound 3b, 3c and 3i showed better anti-itch activity. The compound 3i is safe for normal breast and liver normal cells, but it has high cytotoxicity on normal lung cell. CONCLUSION: The synthesized compounds have dual anti-cancer and anti-itch activity, so the development of drug with dual anti-tumor and anti-itch property is possible.

[Extemporaneous magistral formulas for the topical treatment of pruritus : Proven and new options]. / Magistralrezepturen zur topischen Therapie des Pruritus : Bewährtes und Neues.

The treatment of pruritus, primarily chronic pruritus, is often difficult and must be treated simultaneously with the cause of pruritus and the individual demands of the skin. Due to the chronicity, a combination of systemic therapies, different active ingredients and basic formulas must be used in local therapies and adjusted during the course of the treatment. There are still therapeutic gaps, which can be closed by the use of extemporaneous preparations. Magistral formulas, which are already checked for plausibility, should be preferred over individual prescriptions. In the following, different therapeutic options in daily practice by using extemporaneous formulas from the NRF (New German Pharmacopoeia for compounded medications) are presented.

Selective CB2 agonists with anti-pruritic activity: discovery of potent and orally available bicyclic 2-pyridones.

The CB2 receptor has emerged as a potential target for the treatment of pruritus as well as pain without CB1-mediated side effects. We previously identified 2-pyridone derivatives 1 and 2 as potent CB2 agonists; however, this series of compounds was found to have unacceptable pharmacokinetic profiles with no significant effect in vivo. To improve these profiles, we performed further structural optimization of 1 and 2, which led to the discovery of bicyclic 2-pyridone 18e with improved CB2 affinity and selectivity over CB1. In a mouse pruritus model, 18e inhibited compound 48/80 induced scratching behavior at a dose of 100 mg/kg. In addition, the docking model of 18e with an active-state CB2 homology model indicated the structural basis of its high affinity and selectivity over CB1.

Design, synthesis and anti-itch activity evaluation of aromatic amino acid derivatives as gastrin-releasing peptide receptor antagonists.

Eight aromatic amino acid derivatives (9a-9h) as gastrin-releasing peptide receptor (GRPR) antagonists were designed and synthesized. For the design, the tertiary structure of GRPR was predicted by blast searching in the premise of 1u19 protein as the template. Eight target compounds were docked into the binding pocket to investigate their possible binding interactions. Their anti-itch activities were tested by intrathecal injection using Kunming mice as experimental animals and chloroquine phosphate as a modeling medium. Compounds 9e and 9f significantly inhibited scratching behaviors. The anti-itch activities of these compounds decreased with the following sequence: 9e > 9f = 9d > 9b > 9g > 9a > 9h > 9c predicted by computer-aided drug design (CADD) and 9e > 9f > 9b > 9h > 9g > 9d > 9a > 9c evaluated by preliminary test. They were broadly in line with activity order pretested by CADD. It showed that the predicted tertiary structure of GRPR could be used for antipruritic drug design.

SAR and biological evaluation of 3-azabicyclo[3.1.0]hexane derivatives as µ opioid ligands.

3-Azabicyclo[3.1.0]hexane compounds were designed as novel achiral µ opioid receptor ligands for the treatment of pruritus in dogs. In this paper, we describe the SAR of this class of opioid ligand, highlighting changes to the lead structure which led to compounds having picomolar binding affinity, selective for the µ receptor over δ and κ subtypes. Some subtleties of functional activity will also be described.