Entropy driven cooperativity effect in multi-site drug optimization targeting SARS-CoV-2 papain-like protease

Papain-like protease (PLpro), a non-structural protein encoded by SARS-CoV-2, is an important therapeutic target. Regions 1 and 5 of an existing drug, GRL0617, can be optimized to produce cooperativity with PLpro binding, resulting in stronger binding affinity. This work investigated the origin of the cooperativity using molecular dynamics simulations combined with the interaction entropy (IE) method. The regions' improvement exhibits cooperativity by calculating the binding free energies between the complex of PLpro-inhibitor. The thermodynamic integration method further verified the cooperativity generated in the drug improvement. To further determine the specific source of cooperativity, enthalpy and entropy in the complexes were calculated using molecular mechanics/generalized Born surface area and IE. The results show that the entropic change is an important contributor to the cooperativity. Our study also identified residues P248, Q269, and T301 that play a significant role in cooperativity. The optimization of the inhibitor stabilizes these residues and minimizes the entropic loss, and the cooperativity observed in the binding free energy can be attributed to the change in the entropic contribution of these residues. Based on our research, the application of cooperativity can facilitate drug optimization, and provide theoretical ideas for drug development that leverage cooperativity by reducing the contribution of entropy through multi-locus binding.

 

Comments:

It seems like you've provided a detailed summary of a research study investigating the cooperativity between the papain-like protease (PLpro), a non-structural protein encoded by SARS-CoV-2, and an existing drug called GRL0617. The study utilized molecular dynamics simulations, interaction entropy (IE) method, and thermodynamic integration method to explore the binding interactions between PLpro and the inhibitor.

Here's a breakdown of the key findings and methods used in the study:

1. **Target and Drug:** The study focused on PLpro, a protein encoded by SARS-CoV-2, as a therapeutic target. The drug in question is GRL0617.

2. **Cooperativity Enhancement:** Regions 1 and 5 of the drug were optimized to enhance cooperativity with PLpro binding, resulting in stronger binding affinity.

3. **Methods Used:**
   - **Molecular Dynamics Simulations:** These were employed to simulate the interactions between PLpro and the inhibitor.
   - **Interaction Entropy (IE) Method:** This method was utilized to understand the origin of cooperativity by calculating binding free energies between the PLpro-inhibitor complex.
   - **Thermodynamic Integration Method:** This method was used to further verify the cooperativity observed in the drug improvement by calculating binding free energies.

4. **Specific Source of Cooperativity:** The study aimed to determine the specific source of cooperativity by calculating enthalpy and entropy in the complexes using molecular mechanics/generalized Born surface area and IE. The results indicated that entropic changes, particularly the entropic contribution of certain residues (P248, Q269, and T301), played a significant role in cooperativity.

5. **Role of Specific Residues:** Residues P248, Q269, and T301 were identified as key players in the observed cooperativity. The optimization of the inhibitor stabilized these residues and minimized entropic loss, contributing to the overall increase in binding affinity.

6. **Implications:** The research suggests that understanding and leveraging cooperativity, particularly by reducing the contribution of entropy through multi-locus binding, can facilitate drug optimization. This study provides theoretical insights that can be applied in drug development, specifically in optimizing drugs for SARS-CoV-2 by targeting PLpro.

In summary, the study used advanced computational techniques to explore the interactions between PLpro and an existing drug, leading to insights that can be valuable in the development of more effective therapeutic agents against SARS-CoV-2.

Related Products

Cat.No.	Product Name	Information
S6845	GRL0617	GRL0617 is a potent, selective and competitive noncovalent inhibitor of severe acute respiratory syndrome (SARS-CoV) papain-like protease (PLPro)/deubiquitinase with IC50 of 0.6 μM and Ki of 0.49 μM. GRL0617 inhibits SARS-CoV viral replication in Vero E6 cells with EC50 of 15 microM and has no associated cytotoxicity.

Related Targets

SARS-CoV DUB