5-HT receptor antagonists. Design, synthesis, and structure-activity relationship of substituted 2-(1-methyl-4-piperazinyl)pyridines.

In this study, we present the discovery and pharmacological characterization of a new series of 6-piperazinyl-7-azaindoles. These compounds demonstrate potent antagonism and selectivity against the 5-HT receptor. Our research primarily focuses on optimizing the lead structure and investigating the structure-activity relationship (SAR) of these compounds.

3D proteochemometrics: using three-dimensional information of proteins and ligands to address aspects of the selectivity of serine proteases.

The high similarity between certain sub-pockets of serine proteases may lead to low selectivity of protease inhibitors. Therefore the application of proteochemometrics (PCM), which quantifies the relationship between protein/ligand descriptors and affinity for multiple ligands and targets simultaneously, is useful to understand and improve the selectivity profiles of potential inhibitors. In this study, protein field-based PCM that uses knowledge-based and WaterMap derived fields to describe proteins in combination with 2D (RDKit and MOE fingerprints) and 3D (4 point pharmacophoric fingerprints and GRIND) ligand descriptors was used to model the bioactivities of 24 homologous serine proteases and 5863 inhibitors in an integrated fashion.

1-Sulfonyl-6-Piperazinyl-7-Azaindoles as potent and pseudo-selective 5-HT6 receptor antagonists.

A series of 1-Sulfonyl-6-Piperazinyl-7-Azaindoles, showing strong antagonistic activity to 5-HT6 receptor (5-HT6R) was synthesized and characterized. The series was optimized to reduce activity on D2 receptor. Based on the selectivity against this off-target and the analysis of the ADME-tox profile, compound 1c was selected for in vivo efficacy assessment, which demonstrated procognitive effects as shown in reversal of scopolamine induced amnesia in an elevated plus maze test in mice.

Visually interpretable models of kinase selectivity related features derived from field-based proteochemometrics.

Achieving selectivity for small organic molecules toward biological targets is a main focus of drug discovery but has been proven difficult, for example, for kinases because of the high similarity of their ATP binding pockets. To support the design of more selective inhibitors with fewer side effects or with altered target profiles for improved efficacy, we developed a method combining ligand- and receptor-based information. Conventional QSAR models enable one to study the interactions of multiple ligands toward a single protein target, but in order to understand the interactions between multiple ligands and multiple proteins, we have used proteochemometrics, a multivariate statistics method that aims to combine and correlate both ligand and protein descriptions with affinity to receptors.

Design and evaluation of substrate-based octapeptide and non substrate-based tetrapeptide inhibitors of dengue virus NS2B-NS3 proteases.

A series of 45 peptide inhibitors was designed, synthesized, and evaluated against the NS2B-NS3 proteases of the four subtypes of dengue virus, DEN-1-4. The design was based on proteochemometric models for Michaelis (Km) and cleavage rate constants (kcat) of protease substrates. This led first to octapeptides showing submicromolar or low micromolar inhibitory activities on the four proteases.