Molecular dynamics: a powerful tool for studying the medicinal chemistry of ion channel modulators.

Molecular dynamics (MD) simulations allow researchers to investigate the behavior of desired biological targets at ever-decreasing costs with ever-increasing precision. Among the biological macromolecules, ion channels are remarkable transmembrane proteins, capable of performing special biological processes and revealing a complex regulatory matrix, including modulation by small molecules, either endogenous or exogenous. Recently, given the developments in ion channel structure determination and accessibility of bio-computational techniques, MD and related tools are becoming increasingly popular in the intense research area regarding ligand-channel interactions. This review synthesizes and presents the most important fields of MD involvement in investigating channel-molecule interactions, including, but not limited to, deciphering the binding modes of ligands to their ion channel targets and the mechanisms through which chemical compounds exert their effect on channel function. Special attention is devoted to the importance of more elaborate methods, such as free energy calculations, while principles regarding drug design and discovery are highlighted. Several technical aspects involving the creation and simulation of channel-molecule MD systems (ligand parameterization, proper membrane setup, system building, etc.) are also presented.

Molecular determinants of chemical modulation of two-pore domain potassium channels.

The K+ ion channels comprising the two-pore domain (K2P) family have specific biophysical roles in generating the critical regulatory K+ current. Ion flow through K2P channels and, implicitly, channel regulation is mediated by diverse metabolic and physical inputs such as mechanical stimulation, interaction with lipids or endogenous regulators, intra- or extracellular pH, and phosphorylation, while their function can be finely tuned by chemical compounds. In the latter category, some drug-channel interactions can lead to side effects or have clinical action, while identifying novel chemical modulators of K2Ps is an area of intense research. Due to their cellular and therapeutic importance, much attention was turned to these channels in recent years and several experimental approaches have pinpointed the molecular determinants of K2P chemical modulation. Given their unique structural features and properties, chemical modulators act on K2P channels in multiple and diverse ways. In this review, the particularities of K2P modulation by chemical compounds, such as binding modality, affinity, or position, are identified, synthesized, and linked to structural and functional properties in order to refer to how activators and blockers modify channel function and vice versa, focusing on specificity related to protein structure (and its modification) and cross-linking information among different subfamilies.