Safety from Medicinal Chemistry Scaffolds


Application Note

Virtual Screening to Identify Calcium Channel Blockers


Seeking Improved Safety from Medicinal Chemistry Scaffolds

The first marketed selective T-type calcium channel blocker mibefradil was withdrawn due to adverse drug interactions, prompting the search for new scaffolds. This paper describes a workflow using Reaxys® Medicinal Chemistry to assess chemical and biological information and the Reaxys Flat File as a source of chemical diversity for ligand-based virtual screening.

New TCCBs with new scaffolds are required to understand the exact role of T-type Ca2+ channels in cellular functions.

Neuronal voltage-gated calcium channels play a central role in the control of cellular excitability and a number of calcium-dependent cellular functions, including gene transcription and transmitter release. Subtypes of high voltage-activated Ca2+ channels play important roles in synaptic transmission in the nervous system. However, the main proposed functions of low voltage-activated Ca2+ channels—also called transient or T-type calcium channels—include promotion of Ca2+-dependent burst firing, generation of low-amplitude intrinsic neuronal oscillations, elevation of Ca2+entry and boosting of dendritic signals, which contribute to neuronal pacemaker activity, wakefulness, seizure susceptibility or integration of sensory information, including pain (1–3)
Huguenard, J.R. and Prince, D.A. (1992)
A novel T-type current underlies prolonged Ca2+- dependent burst firing in GABAergic neurons of rat thalamic reticular nucleus. J Neurosci 12: 3804–3817.
Perez-Reyes E. (2003)
Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 83: 117–161.
Bourinet, E. and Zamponi, G.W. (2005)
Voltage-gated calcium channels as targets for analgesics. Curr Top Med Chem 5: 539-546.
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Three structurally and functionally distinctive T-type calcium channels have been cloned. These are denoted as voltage-dependent Ca2+ channel Cav3.1, Cav3.2 and Cav3.3. Of these isoforms, Cav3.2 has been identified as a good target to identify new classes of analgesic drugs for pathological pain syndromes (3)
Bourinet, E. and Zamponi, G.W. (2005)
Voltage-gated calcium channels as targets for analgesics. Curr Top Med Chem 5: 539-546.
. However, only limited progress has been made in the quest to identify both potent and selective compounds for T-type channel blockade. The Ca2+ channel blockers such as flunarizine, U-92032, nicardipine and mibefradil (Figure 1) have been reported as active T-type Ca2+channel blockers (TCCBs).

Structures of some known active TCCBs | Elsevier Whitepaper
Figure 1. Structures of some known active T-type calcium channel blockers (TCCBs)

Mibefradil, the first marketed selective TCCB inhibits the T-type Ca2+ channels 10−30 times more potently that L-type Ca2+ channels. It was finally withdrawn due to its pharmacokinetic interactions with other drugs metabolized by cytochromes P450 3A4 and 2D6. Therefore, new TCCBs having new scaffolds are required to understand the exact role of T-type Ca2+ channel in cellular functions.
Herein, we report the application of Reaxys Medicinal Chemistry as an essential starting point for gathering critical biological and chemical information required to feed into ligand-based virtual screening (Figure 2). The data generated was used with bi-dimensional 2D pharmacophoric fingerprint software to identify a new series of TCCBs. The virtual hits were put through a functional assay on the Cav3.2 isoform to assess their biological activity.

Workflow to identify new TCCBs | Elsevier Whitepaper
Figure 2. Workflow to identify new T-type calcium channel blockers (TCCBs)