Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors

by Selleckchem | Dec 17 2023

Phosphodiesterase-4 (PDE4) and PDE5 responsible for the hydrolysis of intracellular cAMP and cGMP, respectively, are promising targets for therapeutic intervention in a wide variety of diseases. Here, we report the discovery of novel, drug-like PDE4 inhibitors by performing a high-throughput drug repurposing screening of 2560 approved drugs and drug candidates in clinical trial studies. It allowed us to identify eight potent PDE4 inhibitors with IC50 values ranging from 0.41 to 2.46 μM. Crystal structures of PDE4 in complex with four compounds, namely ethaverine hydrochloride (EH), benzbromarone (BBR), CX-4945, and CVT-313, were further solved to elucidate molecular mechanisms of action of these new inhibitors, providing a solid foundation for optimizing the inhibitors to improve their potency as well as selectivity. Unexpectedly, selectivity profiling of other PDE subfamilies followed by crystal structure determination revealed that CVT-313 was also a potent PDE5 inhibitor with a binding mode similar to that of tadalafil, a marketed PDE5 inhibitor, but distinctively different from the binding mode of CVT-313 with PDE4. Structure-guided modification of CVT-313 led to the discovery of a new inhibitor, compound 2, with significantly improved inhibitory activity as well as selectivity towards PDE5 over PDE4. Together, these results highlight the utility of the drug repurposing in combination with structure-based drug design in identifying novel inhibitors of PDE4 and PDE5, which provides a prime example for efficient discovery of drug-like hits towards a given target protein.

Comments:

The passage describes a study focused on identifying novel inhibitors for two phosphodiesterase enzymes, PDE4 and PDE5, through a combination of high-throughput drug repurposing screening and structure-based drug design. Here's a breakdown of the key findings and methods described in the passage:

### Objective:
- **Identification of PDE4 and PDE5 Inhibitors:** The researchers aimed to find new inhibitors for PDE4 and PDE5, enzymes responsible for hydrolyzing intracellular signaling molecules cAMP and cGMP, respectively. Inhibition of these enzymes can have therapeutic implications in various diseases.

### Methodology:
- **High-Throughput Drug Repurposing Screening:** The study involved screening 2560 approved drugs and drug candidates in clinical trials to identify potential inhibitors for PDE4 and PDE5.

- **Identification of Potent Inhibitors:** Eight potent PDE4 inhibitors were discovered through this screening process. These inhibitors exhibited IC50 values ranging from 0.41 to 2.46 μM, indicating their effectiveness in inhibiting the target enzymes.

- **Structural Analysis:** Crystal structures of PDE4 in complex with four compounds (ethaverine hydrochloride, benzbromarone, CX-4945, and CVT-313) were solved. This structural analysis helped in understanding the molecular mechanisms of action of these inhibitors.

- **Unexpected Discovery:** CVT-313, one of the identified PDE4 inhibitors, was also found to be a potent PDE5 inhibitor. Its binding mode with PDE5 was similar to that of tadalafil, a marketed PDE5 inhibitor, but distinct from its binding mode with PDE4.

- **Structure-Guided Modification:** The researchers used the structural information to modify CVT-313, leading to the discovery of a new inhibitor called compound 2. This compound exhibited significantly improved inhibitory activity against PDE5 and demonstrated selectivity over PDE4.

### Key Findings:
- **Identification of Novel Inhibitors:** The study identified eight new inhibitors for PDE4, which could potentially be used for therapeutic purposes in diseases where modulation of cAMP signaling is beneficial.

- **Dual Inhibition:** CVT-313 was identified as a dual inhibitor, effectively targeting both PDE4 and PDE5. This dual inhibitory activity could have applications in diseases where both cAMP and cGMP pathways need to be modulated.

- **Structure-Guided Design:** The researchers used the structural information from the complexes to design a new inhibitor (compound 2) with improved potency and selectivity. This highlights the importance of structure-based drug design in optimizing drug candidates.

### Significance:
- **Efficient Drug Discovery:** The study demonstrates the utility of drug repurposing combined with structural analysis for efficient drug discovery. By repurposing existing drugs and optimizing their structures based on crystallographic data, the researchers were able to identify promising drug candidates for further development.

In summary, this study provides valuable insights into the discovery of potent and selective inhibitors for PDE4 and PDE5, showcasing the importance of a multidisciplinary approach that integrates high-throughput screening, structural biology, and rational drug design in the drug discovery process.