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PROTAC-Design-Evaluator (PRODE): An Advanced Method for In-Silico PROTAC Design
Ben Geoffrey A S1, Deepak Agrawal1, Nagaraj M Kulkarni1
1Sravathi AI Technology Pvt. Ltd., 63-B, Bommasandra Industrial Area, Bengaluru, Karnataka 560099, India.
ACS Omega
|March 25, 2024
Summary
We developed a novel computational method, PROTAC-Designer-Evaluator (PRODE), for designing proteolysis-targeting chimeras (PROTACs). PRODE accurately models PROTACs and ternary complexes, advancing in-silico drug discovery for undruggable targets.
Area of Science:
- Biochemistry
- Computational Chemistry
- Drug Discovery
Background:
- Proteolysis-targeting chimeras (PROTACs) offer a novel therapeutic strategy for targeting previously undruggable proteins.
- Designing effective PROTACs requires precise control over ternary complex formation between the target protein, E3 ligase, and the PROTAC molecule.
- Current in-silico methods for PROTAC design are limited in their ability to accurately predict functional properties and complex stability.
Purpose of the Study:
- To present a novel in-silico method, PROTAC-Designer-Evaluator (PRODE), for the rational design and evaluation of PROTACs.
- To validate the PRODE methodology by accurately reproducing known PROTAC-target-ligase interactions and thermodynamic properties.
- To demonstrate the application of PRODE in designing a novel PROTAC for FGFR1 degradation.
Main Methods:
- Development of the PROTAC-Designer-Evaluator (PRODE) computational platform.
- Utilizing theoretical/computational methodologies to model PROTAC binding modes and ternary complex structures.
- Employing thermal titration molecule dynamics (TTMD) to assess the stability of PROTAC-mediated ternary complexes.
- Applying PRODE to design a PROTAC targeting FGFR1 in conjunction with the MDM2 E3 ligase.
Main Results:
- The PRODE method successfully reproduced the binding mode, ternary complex structure, and thermodynamic favorability (ΔG) for a known BRD4-VHL-PROTAC system.
- TTMD analysis demonstrated PRODE's capability to differentiate the stability of various PROTAC-mediated ternary complexes.
- A novel PROTAC design for FGFR1 degradation using the PRODE platform was successfully generated.
Conclusions:
- PRODE represents a significant advancement in in-silico PROTAC design, offering enhanced accuracy and predictive power.
- The methodology validates the use of computational approaches for optimizing PROTAC efficacy and stability.
- PRODE facilitates the development of targeted protein degradation therapies for challenging targets like FGFR1 in cancer treatment.
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