Human Cav1.3 (hCav1.3) is of great interest as a potential target for Parkinson’s disease. However, common medications like dihydropyridines (DHPs), a kind of classic calcium channel blocker, have poor selectivity to hCav1.3 in clinical treatment, mainly due to being implicated in cardiovascular side-effects mediated by human Cav1.2 (hCav1.2). Recently, pyrimidine-2,4,6-triones (PYTs) have received extensive attention as prominent selective inhibitors to hCav1.3. In this study, we describe the selectivity mechanism of PYTs for hCav1.2 and hCav1.3 based on molecular dynamic simulation methods. Our results reveal that the van der Waals (vdW) interaction was the most important force affecting selectivity. Moreover, the hydrophobic interaction was more conducive to the combination. The highly hydrophobic amino acid residues on hCav1.3, such as V162 (IR1), L303 (IR2), M481 (IR3), and F484 (IR3), provided the greatest contributions in the binding free energy. On the other hand, the substituents of a halogen-substituted aromatic ring, cycloalkyl and norbornyl on PYTs, which are pertinent to the steric hindrance of the compounds, played core roles in the selectivity and affinity for hCav1.3, whereas strong polar substituents needed to be avoided. The findings could provide valuable information for designing more effective and safe medicines for Parkinson’s disease.

Voltage-gated sodium channels (VGSCs, or Nav) are important determinants of action potential generation and propagation. Efforts are underway to develop medicines targeting different channel subtypes for the treatment of related channelopathies. However, a high degree of conservation across its nine subtypes could lead to the off-target adverse effects on skeletal and cardiac muscles due to acting on primary skeletal muscle sodium channel Nav1.4 and cardiac muscle sodium channel Nav1.5, respectively. For a long evolutionary process, some peptide toxins from venoms have been found to be highly potent yet selective on ion channel subtypes and, therefore, hold the promising potential to be developed into therapeutic agents. In this research, all-atom molecular dynamic methods were used to elucidate the selective mechanisms of an analgesic-antitumor β-scorpion toxin (AGAP) with human Nav1.4 and Nav1.5 in order to unravel the primary reason for the production of its adverse reactions on the skeletal and cardiac muscles. Our results suggest that the rational distribution of residues with ring structures near position 38 and positive residues in the C-terminal on AGAP are critical factors to ensure its analgesic efficacy. Moreover, the substitution for residues with benzene is beneficial to reduce its side effects.