Prediction Models for Agonists and Antagonists of Molecular Initiation Events for Toxicity Pathways Using an Improved Deep-Learning-Based Quantitative Structure–Activity Relationship System

In silico approaches have been studied intensively to assess the toxicological risk of various chemical compounds as alternatives to traditional in vivo animal tests. Among these approaches, quantitative structure–activity relationship (QSAR) analysis has the advantages that it is able to construct models to predict the biological properties of chemicals based on structural information. Previously, we reported a deep learning (DL) algorithm-based QSAR approach called DeepSnap-DL for high-performance prediction modeling of the agonist and antagonist activity of key molecules in molecular initiating events in toxicological pathways using optimized hyperparameters. In the present study, to achieve high throughput in the DeepSnap-DL system–which consists of the preparation of three-dimensional molecular structures of chemical compounds, the generation of snapshot images from the three-dimensional chemical structures, DL, and statistical calculations—we propose an improved DeepSnap-DL approach. Using this improved system, we constructed 59 prediction models for the agonist and antagonist activity of key molecules in the Tox21 10K library. The results indicate that modeling of the agonist and antagonist activity with high prediction performance and high throughput can be achieved by optimizing suitable parameters in the improved DeepSnap-DL system.

Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 Core

Activation of the neuropeptide S receptor (NPSR) system has been shown to produce anxiolytic-like actions, arousal, and enhance memory consolidation, whereas blockade of the NPSR has been shown to reduce relapse to substances of abuse and duration of anesthetics. We report here the discovery of a novel core scaffold (+) N-benzyl-3-(2-methylpropyl)-1-oxo-3-phenyl-1H,3H,4H,5H,6H,7H-furo[3,4-c]pyridine-5-carboxamide with potent NPSR antagonist activity in vitro. Pharmacokinetic parameters demonstrate that 14b reaches pharmacologically relevant levels in plasma and the brain following intraperitoneal (i.p.) administration, but is cleared rapidly from plasma. Compound 14b was able to block NPS (0.3 nmol)-stimulated locomotor activity in C57/Bl6 mice at 3 mg/kg (i.p.), indicating potent in vivo activity for the structural class. This suggests that 14b can serve as a useful tool for continued mapping of the pharmacological functions of the NPS receptor system.

Comparison of cervical muscle isometric force between migraine subgroups or migraine-associated neck pain: a controlled study

This study aimed to verify if migraine frequency or migraine-associated neck pain were associated with a reduction of normalized force and altered electromyographic activity during maximal cervical muscle isometric contractions. Additionally, it aimed to assess the correlation of normalized isometric force with years with migraine, headache frequency, headache intensity, migraine-related disability, and severity of cutaneous allodynia. The sample comprises 71 women with migraine (40/31 episodic/chronic, 42/18 with/without neck pain) and 32 women without headache. Cervical muscle isometric force in flexion, extension, and lateral flexion was assessed synchronized with the acquisition of superficial electromyography from the cervical muscles. Women with episodic migraine presented lower normalized isometric force in extension, flexion, and right and left lateral flexions than controls (P < 0.05). Women with migraine and neck pain exhibited lower cervical extension and right/left lateral-flexions normalized isometric force than controls (P < 0.05). No significant differences were observed in antagonist activity. Normalized isometric force in all directions showed weak to moderate correlations with the severity of self-reported symptoms of cutaneous allodynia (− 0.25 ≥ r ≥ − 0.39). No additional linear correlation with clinical migraine features was observed. In conclusion, cervical muscle weakness may be associated with episodic migraine and neck pain concurrent with migraine attacks without altered antagonist activity. Additionally, it may also be related to the severity of cutaneous allodynia.

Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes

Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood–brain barrier penetration hinder their application. Targeted nanoparticle delivery systems are being tapped for their ability to improve the delivery of therapeutics into the brain non-invasively. We have developed a family of mannosylated glycoliposome delivery systems for targeted drug delivery applications. Herein, we demonstrate via in vivo distribution studies the potential of these glycoliposomes to improve the utility of CNS active therapeutics using dynantin, a potent and selective dynorphin peptide analogue antagonist of the kappa opioid receptor (KOR). Glycoliposomal entrapment protected dynantin against known rapid metabolic degradation and ultimately improved brain levels of the peptide by approximately 3–3.5-fold. Moreover, we linked this improved brain delivery with improved KOR antagonist activity by way of an approximately 30–40% positive modulation of striatal dopamine levels 20 min after intranasal administration. Overall, the results clearly highlight the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the CNS.

Prediction of Molecular Interactions And Physicochemical Properties Relevant For Vasopressin V2 Receptor Antagonism

We have developed two ligand and receptor-based computational approaches to study the physicochemical properties relevant to the biological activity of vasopressin V2 receptor (V2R) antagonist and eventually to predict the expected binding mode to V2R. The obtained Quantitative Structure Activity Relationship (QSAR) model showed a correlation of the antagonist activity with the hydration energy (EH2O) , the polarizability (P) and the calculated partial charge on atom N7 (q6) of the common substructure. The first two descriptors showed a positive contribution to antagonist activity, while the third one had a negative contribution. V2R was modeled and further relaxed on a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocoline (POPC) membrane by molecular dynamics simulations. The receptor antagonist complexes were guessed by molecular docking, and the stability of the most relevant structures were also evaluated by molecular dynamics simulations. As a result, amino acid residues Q96, W99, F105, K116, F178, A194, F307, and M311 were identified with the probably most relevant antagonist-receptor interactions on the studied complexes. The proposed QSAR model could explain the molecular properties relevant to the antagonist activity. The contributions to the antagonist-receptor interaction appeared also in agreement with the binding mode of the complexes obtained by molecular docking and Molecular Dynamics. These models will be used in further studies to look for new V2R potential antagonist molecules.

Synthesis and Development of Indole Based 5-HT3 Receptor Antagonists as Anti-Emetic Drugs in Oncology: An Update

: An important group of anti-emetic drugs used in the treatment of nausea and vomiting after chemotherapy contains an indole moiety in their structures, working as 5-hydroxytryptamine type 3 serotonin receptor antagonist (5-HT3). This revision is focused on compounds bearing an indole core that present a 5-HT3 receptor antagonist activity that has been successfully used as anti-emetic drugs, reducing chemotherapy adverse secondary effects during cancer treatment. Their synthesis, biological activities, and some outstanding characteristics are discussed, affording a general outlook towards the development of more efficient anti-emetic drugs.