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Elucidation of the Mechanism of Action of New Drug Candidates on Target Proteins

中島, 康祐 筑波大学 DOI:10.15068/0002005698

2022.11.25

概要

Drug discovery, beneficial in basic science research, involves drug optimization to identify compounds with excellent profiles and to elucidate mechanisms of action on their target proteins by suitable pharmacological studies. Proteins undergo conformational changes under various biological conditions, and the effect of the compound on target proteins having different conformations varies. Additionally, conformational changes involved in protein function are often closely related to various diseases. Here, the compounds acting on the same target protein may have different therapeutic effects based on changes in their targeted protein conformations. Therefore, to obtain valuable drug candidates, a number of factors other than biological assay is necessary such as, identification of multiple compounds with various mechanisms of action against their target proteins, detailed analysis of their mechanism of action, and determining the mechanism optimal for the desired drug. Here, I have identified several compounds with novel mechanisms of action in two drug discovery programs. In addition, I elucidated the mechanism of action via suitable pharmacological studies for each target and presented data that form the basis for understanding the diseases and their underlying phenomena of life.

Chapter I describes a novel mode of inhibition of phosphodiesterase type (PDE) 2A inhibitors. PDE2A is an enzyme that hydrolyzes cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) and has attracted attention as a drug target molecule in central nervous system diseases that affect memory, learning, and cognition. PDE2A has a GAF (cGMP-specific phosphodiesterases, adenylyl cyclases and FhlA) domain that binds to cGMP, which then increases the hydrolytic activity of the substrates, cGMP and cAMP. Thus, positive feedback of the catalytic activity to hydrolyze cyclic nucleotides, cAMP and cGMP, occurs in the presence of appropriate concentrations of cGMP, resulting in a “brake” that attenuates downstream cyclic nucleotide signaling. I found that some previously reported PDE2A inhibitors had reduced inhibitory activity in the presence of cGMP at concentrations (70 nM) lower than those effective for positive feedback (4 μM). This impairment depended on the presence of the GAF domains but was not attributed to the binding of the inhibitors to these domains. Notably, I identified novel PDE2A inhibitors that did not exhibit this behavior; i.e., the inhibitory effects of these compounds were as strong at a lower concentration of cGMP (70 nM) as at a higher concentration (4 μM). cGMP levels in the cerebrospinal fluid are lower in patients with schizophrenia and Alzheimer's disease than in healthy subjects, which may partly explain the symptoms. This suggests that PDE2A inhibitors with the above novel mode of inhibition may be more effective than other PDE2A inhibitors in normalizing low cGMP levels in these diseases.

Chapter II describes the discovery of novel hyperpolarization-activated cyclic nucleotide-gated (HCN) 4 channel blockers with blocking kinetics and binding properties that have not been previously reported. The HCN4 channel regulates the heart rate by generating a pacemaker current called “If” in the sinoatrial node (SAN) near the right atrium. HCN4 blockers such as ivabradine and ZD7288 are widely used to study various cardiac diseases. These blockers have a variety of channel-state dependencies and binding sites, suggesting that other unique molecules may be identified, which will further help in understanding HCN properties and drug discovery for HCN4 blockers. Therefore, I performed a random screening of 16,000 small molecule compounds using an automated patch clamp system and identified novel HCN4 blockers. The blocking kinetics and binding properties of these molecules were determined by electrophysiological studies and site-directed mutagenesis, respectively, which indicated various blocking profiles. These blocking profiles were different from those of ivabradine and ZD7288. Notably, mutagenesis analysis demonstrated that blockers that were more potent when the channel was open were associated with the C478 residue, located in the pore cavity region near the cellular surface of the plasma membrane. In addition, blockers that were less potent when the channel was open were associated with residues Y506 and I510, located in the intracellular region of the pore gate. Thus, identification of novel HCN4 blockers for the first time through random screening was carried out, and further profiling analysis of these blockers provided the unique molecular insights in the drug-binding modes of HCN4.

In summary, these studies identified several novel therapeutic candidate compounds, PDE2A inhibitors and HCN4 blockers, which were different from known compounds by their mechanisms of action on their target proteins and proposed new insights into the biological regulatory mechanisms involved in the pathology. Pharmacological studies to elucidate these novel compounds and mechanisms of action are expected to lead not only to the development of drugs in their respective therapeutic areas but also to the functional analysis of target proteins and further understanding of disease mechanisms.

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