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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.

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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.

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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.