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Development of Receptor Desolvation Scoring and Covalent Sampling in DOCK 6: Methods Evaluated on a RAS Test Set.

Y Stanley Tan1, Mayukh Chakrabarti1, Reed M Stein2

  • 1NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., P.O. Box B, Frederick 21702, Maryland, United States.

Journal of Chemical Information and Modeling
|January 6, 2025
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Summary
This summary is machine-generated.

This study introduces new molecular docking features for RAS proteins, improving cancer drug discovery by accounting for solvation and covalent binding. These advancements enhance the accuracy of predicting drug-target interactions for oncogenic RAS.

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Area of Science:

  • Computational chemistry
  • Structural biology
  • Drug discovery

Background:

  • RAS proteins are crucial cancer targets, with many inhibitors binding covalently.
  • Molecular docking is vital for drug discovery, but accurately modeling solvation and covalent interactions remains challenging.
  • Water molecules significantly influence small molecule binding to RAS proteins.

Purpose of the Study:

  • To implement and evaluate a receptor desolvation scoring function and a covalent docking algorithm in DOCK 6.
  • To assess the impact of solvation effects (GIST and 3D-RISM) on molecular docking accuracy for RAS proteins.
  • To validate a covalent docking algorithm (attach-and-grow) for RAS systems.

Main Methods:

  • Developed a RAS test set of 138 protein structures and 2 DNA structures.
  • Implemented receptor desolvation scoring using GIST and 3D-RISM methods.
  • Integrated a covalent docking algorithm (attach-and-grow) into DOCK 6.
  • Evaluated performance using pose reproduction, cross-docking, and enrichment calculations.

Main Results:

  • Receptor desolvation using GIST improved enrichment in 51% of systems; 3D-RISM improved it in 44%.
  • 3D-RISM desolvation increased pose reproduction success rate by 1.8% compared to no desolvation.
  • Covalent docking showed similar pose reproduction success rates to noncovalent docking, with minor variations based on ligand conformation.
  • A proof-of-concept covalent virtual screen of 3.4 million compounds was performed.

Conclusions:

  • Accounting for receptor desolvation offers a small but significant improvement in molecular docking enrichment and pose reproduction for RAS proteins.
  • The implemented covalent docking algorithm is effective for RAS systems.
  • These advancements in DOCK 6 enhance its utility for cancer drug discovery targeting RAS proteins.