Marine Toxins Targeting Ion Channels

This introductory minireview points out the importance of ion channels for cell communication. The basic concepts on the structure and function of ion channels triggered by membrane voltage changes, the so-called voltage-gated ion channels (VGICs), as well as those activated by neurotransmitters, the so-called ligand-gated ion channel (LGICs), are introduced. Among the most important VGIC superfamiles, we can name the voltage-gated Na⁺ (Na_V), Ca²⁺ (Ca_V), and K⁺ (K_V) channels. Among the most important LGIC super families, we can include the Cys-loop or nicotinicoid, the glutamate-activated (GluR), and the ATP-activated (P2X_nR) receptor superfamilies. Ion channels are transmembrane proteins that allow the passage of different ions in a specific or unspecific manner. For instance, the activation of Na_V, Ca_V, or K_V channels opens a pore that is specific for Na⁺, Ca²⁺, or K⁺, respectively. On the other hand, the activation of certain LGICs such as nicotinic acetylcholine receptors, GluRs, and P2X_nRs allows the passage of cations (e.g., Na⁺, K⁺, and/or Ca²⁺), whereas the activation of other LGICs such as type A γ-butyric acid and glycine receptors allows the passage of anions (e.g., Cl⁻ and/or HCO₃⁻). In this regard, the activation of Na_V and Ca_V as well as ligand-gated cation channels produce membrane depolarization, which finally leads to stimulatory effects in the cell, whereas the activation of K_V as well as ligand-gated anion channels induce membrane hyperpolarization that finally leads to inhibitory effects in the cell. The importance of these ion channel superfamilies is emphasized by considering their physiological functions throughout the body as well as their pathophysiological implicance in several neuronal diseases. In this regard, natural molecules, and especially marine toxins, can be potentially used as modulators (e.g., inhibitors or prolongers) of ion channel functions to treat or to alleviate a specific ion channel-linked disease (e.g., channelopaties).     

Cnidarian Toxins Acting on Voltage-Gated Ion Channels

Voltage-gated ion channels generate electrical activity in excitable cells. As such, they are essential components of neuromuscular and neuronal systems, and are targeted by toxins from a wide variety of phyla, including the cnidarians. Here, we review cnidarian toxins known to target voltage-gated ion channels, the specific channel types targeted, and, where known, the sites of action of cnidarian toxins on different channels.     

Computational Design of High-Affinity Blockers for Sodium Channel NaV1.2 from μ-Conotoxin KIIIA

The voltage-gated sodium channel subtype 1.2 (Na_V1.2) is instrumental in the initiation of action potentials in the nervous system, making it a natural drug target for neurological diseases. Therefore, there is much pharmacological interest in finding blockers of Na_V1.2 and improving their affinity and selectivity properties. An extensive family of peptide toxins from cone snails (conotoxins) block Na_V channels, thus they provide natural templates for the design of drugs targeting Na_V channels. Unfortunately, progress was hampered due to the absence of any Na_V structures. The recent determination of cryo-EM structures for Na_V channels has finally broken this impasse. Here, we use the Na_V1.2 structure in complex with μ-conotoxin KIIIA (KIIIA) in computational studies with the aim of improving KIIIA’s affinity and blocking capacity for Na_V1.2. Only three KIIIA amino acid residues are available for mutation (S5, S6, and S13). After performing molecular modeling and simulations on Na_V1.2–KIIIA complex, we have identified the S5R, S6D, and S13K mutations as the most promising for additional contacts. We estimate these contacts to boost the affinity of KIIIA for Na_V1.2 from nanomole to picomole domain. Moreover, the KIIIA[S5R, S6D, S13K] analogue makes contacts with all four channel domains, thus enabling the complete blocking of the channel (KIIIA partially blocks as it has contacts with three domains). The proposed KIIIA analogue, once confirmed experimentally, may lead to novel anti-epileptic drugs.     

A Molecular Modeling Investigation of the Therapeutic Potential of Marine Compounds as DPP-4 Inhibitors

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by elevated levels of blood glucose due to insulin resistance or insulin-secretion defects. The development of diabetes is mainly attributed to the interaction of several complex pathogenic, genetic, environmental and metabolic processes. Dipeptidyl peptidase-4 (DPP-4) is a serine protease that cleaves X-proline dipeptides from the N-terminus of several polypeptides, including natural hypoglycemic incretin hormones. Inhibition of this enzyme restores and maintains glucose homeostasis, making it an attractive drug target for the management of T2DM. Natural products are important sources of bioactive agents for anti-T2DM drug discovery. Marine ecosystems are a rich source of bioactive products and have inspired the development of drugs for various human disorders, including diabetes. Here, structure-based virtual screening and molecular docking were performed to identify antidiabetic compounds from the Comprehensive Marine Natural Products Database (CMNPD). The binding characteristics of two shortlisted compounds, CMNPD13046 and CMNPD17868, were assessed using molecular dynamics simulations. Thus, this study provides insights into the potential antidiabetic activity and the underlying molecular mechanism of two compounds of marine origin. These compounds could be investigated further for the development of potent DPP-4 inhibitors.     

Investigation of Marine-Derived Natural Products as Raf Kinase Inhibitory Protein (RKIP)-Binding Ligands

Raf kinase inhibitory protein (RKIP) is an essential regulator of the Ras/Raf-1/MEK/ERK signaling cascade and functions by directly interacting with the Raf-1 kinase. The abnormal expression of RKIP is linked with numerous diseases including cancers, Alzheimer’s and diabetic nephropathy. Interestingly, RKIP also plays an indispensable role as a tumor suppressor, thus making it an attractive therapeutic target. To date, only a few small molecules have been reported to modulate the activity of RKIP, and there is a need to explore additional scaffolds. In order to achieve this objective, a pharmacophore model was generated that explores the features of locostatin, the most potent RKIP modulator. Correspondingly, the developed model was subjected to screening, and the mapped compounds from Marine Natural Products (MNP) library were retrieved. The mapped MNPs after ensuing drug-likeness filtration were escalated for molecular docking, where locostatin was regarded as a reference. The MNPs exhibiting higher docking scores than locostatin were considered for molecular dynamics simulations, and their binding affinity towards RKIP was computed via MM/PBSA. A total of five molecules revealed significantly better binding free energy scores than compared to locostatin and, therefore, were reckoned as hits. The hits from the present in silico investigation could act as potent RKIP modulators and disrupt interactions of RKIP with its binding proteins. Furthermore, the identification of potent modulators from marine natural habitat can act as a future drug-discovery source.