In silico identification of small molecule modulators for disruption of Hsp90-Cdc37 protein-protein interaction
Prajakta Prakash Dike1, Shovonlal Bhowmick2, Gaber E Eldesoky3
1Department of Bioinformatics, Rajiv Gandhi Institute of IT and Biotechnology, Bharati Vidyapeeth Deemed University, Pune, India.
Abstract:
The protein-protein interactions (PPIs) in the biological systems are important to maintain a number of cellular processes. Several disorders including cancer may be developed due to dysfunction in the assembly of PPI networks. Hence, targeting intracellular PPIs can be considered as a crucial drug target for cancer therapy. Among the enormous and diverse group of cancer-enabling PPIs, the Hsp90-Cdc37 is prominent for cancer therapeutic development. The successful inhibition of Hsp90-Cdc37 PPI interface can be an important therapeutic option for cancer management. In the current study, a set of more than sixty thousand compounds belong to four databases were screened through a multi-steps molecular docking study in Glide against the Hsp90-Cdc37 interaction interface. The Glide-score and Prime-MM-GBSA based binding free energy of DCZ3112, standard Hsp90-Cdc37 inhibitor were found to be -6.96 and -40.46 kcal/mol, respectively. The above two parameters were used as cut-off score to reduce the chemical space from all successfully docked molecules. Furthermore, the in-silico pharmacokinetics parameters, common-feature pharmacophore analyses and the molecular binding interactions were used to wipe out the inactive molecules. Finally, four molecules were found to be important to modulate the Hsp90-Cdc37 interface. The potentiality of the final four molecules was checked through several drug-likeness characteristics. The molecular dynamics (MD) simulation study explained that all four molecules retained inside the interface of Hsp90-Cdc37. The binding free energy of each molecule obtained from the MD simulation trajectory was clearly explained the strong affection towards the Hsp90-Cdc37. Hence, the proposed molecule might be crucial for successful inhibition of the Hsp90-Cdc37 interface.Communicated by Ramaswamy H. Sarma.
Insights
This study identifies four novel compounds that effectively inhibit the Hsp90-Cdc37 protein-protein interaction, a key target in cancer therapy. These findings offer promising new avenues for developing targeted cancer treatments.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- Protein-protein interactions (PPIs) are vital for cellular processes, and their dysregulation, particularly in cancer, highlights their therapeutic potential.
- The Hsp90-Cdc37 interaction is a significant cancer-enabling PPI, making its inhibition a promising strategy for cancer treatment.
Purpose of the Study:
- To identify novel small molecules capable of inhibiting the Hsp90-Cdc37 protein-protein interaction.
- To computationally screen a large compound library for potential Hsp90-Cdc37 inhibitors.
Main Methods:
- A multi-step virtual screening approach using molecular docking (Glide) and binding free energy calculations (Prime-MM-GBSA).
- In-silico pharmacokinetic and pharmacophore analyses were employed for further filtering.
- Molecular dynamics simulations were performed to assess the stability and binding affinity of the identified compounds.
Main Results:
- Over sixty thousand compounds were screened, leading to the identification of four promising molecules targeting the Hsp90-Cdc37 interface.
- The identified molecules demonstrated favorable binding free energies and stable interactions with the Hsp90-Cdc37 complex during molecular dynamics simulations.
- Drug-likeness and pharmacokinetic properties of the final four compounds were evaluated, suggesting their potential as therapeutic agents.
Conclusions:
- The study successfully identified four novel compounds with strong potential to inhibit the Hsp90-Cdc37 interaction.
- These compounds represent promising candidates for further development as targeted cancer therapeutics.
- The computational methodology employed provides a robust framework for discovering PPI inhibitors.
