KCNT1 Channel Blockers: A Medicinal Chemistry Perspective.

Potassium channels have recently emerged as suitable target for the treatment of epileptic diseases. Among potassium channels, KCNT1 channels are the most widely characterized as responsible for several epileptic and developmental encephalopathies. Nevertheless, the medicinal chemistry of KCNT1 blockers is underdeveloped so far. In the present review, we describe and analyse the papers addressing the issue of KCNT1 blockers' development and identification, also evidencing the pros and the cons of the scientific approaches therein described. After a short introduction describing the epileptic diseases and the structure-function of potassium channels, we provide an extensive overview of the chemotypes described so far as KCNT1 blockers, and the scientific approaches used for their identification.

In Silico Assisted Identification, Synthesis, and In Vitro Pharmacological Characterization of Potent and Selective Blockers of the Epilepsy-Associated KCNT1 Channel.

Gain-of-function (GoF) variants in KCNT1 channels cause severe, drug-resistant forms of epilepsy. Quinidine is a known KCNT1 blocker, but its clinical use is limited due to severe drawbacks. To identify novel KCNT1 blockers, a homology model of human KCNT1 was built and used to screen an in-house library of compounds. Among the 20 molecules selected, five (CPK4, 13, 16, 18, and 20) showed strong KCNT1-blocking ability in an in vitro fluorescence-based assay. Patch-clamp experiments confirmed a higher KCNT1-blocking potency of these compounds when compared to quinidine, and their selectivity for KCNT1 over hERG and Kv7.2 channels. Among identified molecules, CPK20 displayed the highest metabolic stability; this compound also blocked KCNT2 currents, although with a lower potency, and counteracted GoF effects prompted by 2 recurrent epilepsy-causing KCNT1 variants (G288S and A934T). The present results provide solid rational basis for future design of novel compounds to counteract KCNT1-related neurological disorders.

Ligand-based pharmacophore modelling, virtual screening and docking studies to identify potential compounds against FtsZ of Mycobacterium tuberculosis.

BACKGROUND AND INTRODUCTION: Tuberculosis (TB) is caused by Mycobacterium tuberculosis (M.tb) which is the most common cause of death from bacterial illness. Millions of victims of TB infections have been recorded including 20,800 deaths amongst HIV positive individuals. Hence, there is a rising need for new and active compounds against M. tb protein targets especially as there is a persistent resistance to the current drug treatment regime. AIM: This study identifies new potential compounds against the M. tb target protein ftsZ via pharmacophore modelling, QSAR analysis and docking studies. METHOD: Inhibitors with known PIC50 were used as a training set and the pharmacophore features (1 aromatic center, 2 hydrophobic, 2 hydrogen bond acceptors and 1 hydrogen bond donor) were validated against four test set compounds. The identified hits were subjected to rigorous ADMET properties and docked using PyRx. DS visualizer was used in binding interactions study. Stability was measured based on the total number of interactions and preference given to the number of hydrogen bond interactions. RESULTS: Based on the number of interactions, hydrogen bonds, extensive virtual screening and ADMET filtration, 40 compounds have been identified as potential inhibitors of ftsZ with only 3 considered to be the best leads. SIGNIFICANCE OF RESEARCH: The identified compounds have potential of being drug candidate against Mycobacterium tuberculosis and may possess a novel mechanistic route in inhibiting the resistant strains.