3D Pharmacophore-Based Discovery of Novel KV10.1 Inhibitors with Antiproliferative Activity

Abstract

(1) Background: The voltage-gated potassium channel KV10.1 (Eag1) is considered a near- universal tumour marker and represents a promising new target for the discovery of novel anticancer drugs. (2) Methods: We utilized the ligand-based drug discovery methodology using 3D pharmacophore modelling and medicinal chemistry approaches to prepare a novel structural class of KV10.1 inhibitors. Whole-cell patch clamp experiments were used to investigate potency, selectivity, kinetics and mode of inhibition. Anticancer activity was determined using 2D and 3D cell-based models. (3) Results: The virtual screening hit compound ZVS-08 discovered by 3D pharmacophore modelling exhibited an IC50 value of 3.70 µM against KV10.1 and inhibited the channel in a voltage-dependent manner consistent with the action of a gating modifier. Structural optimization resulted in the most potent KV10.1 inhibitor of the series with an IC50 value of 740 nM, which was potent on the MCF-7 cell line expressing high KV10.1 levels and low hERG levels, induced significant apoptosis in tumour spheroids of Colo-357 cells and was not mutagenic. (4) Conclusions: Computational ligand-based drug design methods can be successful in the discovery of new potent KV10.1 inhibitors. The main problem in the field of KV10.1 inhibitors remains selectivity against the hERG channel, which needs to be addressed in the future also with target-based drug design methods.

Molecular Dynamics-Derived Pharmacophore Model Explaining the Nonselective Aspect of KV10.1 Pore Blockers

“…Unfortunately, all of the known K V 10.1 inhibitors also inhibit the highly similar cardiac hERG channel, and therefore these have limited potential for development into anticancer drugs that act through this novel mechanism of action. With the goal being to develop selective K V 10.1 inhibitors as potential anticancer drugs [53], we investigated their binding modes in the K V 10.1 channel pore using advanced molecular modeling methodologies. The creation of the common structure-based pharmacophore model for K V 10.1 inhibitors binding to the channel pore allowed us to compare it with the known hERG ligand-based pharmacophore models and to assess the potential for targeting the K V 10.1 channel pore for the development of K V 10.1-selective anticancer agents.…”

“…Ligands that have been reported to inhibit K V 10.1, but where the mechanism of action is not through the block of the potassium ion flux by binding to the central cavity of the channel, should therefore not fit our pharmacophore model. Our model was tested on such a virtual library (Supporting Information Table S3) that was constructed from ligands collected in a review article [17], with the addition of our newly identified set of K V 10.1 inhibitors [53]. The pharmacophore model identified 16 of 61 active compounds.…”

Anti-tumor pharmacology of natural products targeting mitosis

“…Although the multi-target characteristics of natural products can decrease drug resistance, they complicate mechanistic studies. Currently, many new techniques for target prediction are available, such as reverse molecular docking and 3D pharmacophore modeling techniques 211 , 212 . Wei et al 213 have used the parameters of protein-ligand conformation interaction patterns as important indicators for target prediction and screening; this new strategy for target prediction effectively improved the accuracy of small molecule target identification.…”

Potassium Channels as a Target for Cancer Therapy: Current Perspectives

“… 143 This approach has been particularly helpful for the identification of ligands, targeting membrane proteins. 146 , 147 …”

“… 143 Thus, the combinatory strategy including docking, virtual screening, de novo drug design, molecular simulations and the experimental validation by electrophysiological measures have allowed the development and a successful search for small modulators. 146 , 147 For the K + channels, a three-dimensional structure of representative K + subunits (Kv, K2P, and Kir) has been reported, providing insights into how these channels can be used to design specific modulators for cancer treatment.…”