Beyond Venetoclax Cryptic Pocket Pipeline

Beyond Venetoclax Cryptic Pocket Pipeline identifies and scores cryptic binding pockets in mutant oncogene proteins to assess their dynamic druggability for rational drug design.

Key Features:

• Long-timescale Molecular Dynamics (MD): Uses 100–200 ns MD simulations to sample protein conformational ensembles and reveal transient pocket formations.
• Markov State Modeling (MSM) and Time-Lagged Independent Component Analysis (TICA): Resolves conformational landscapes into metastable macrostates to characterize state-specific pocket behavior.
• Voxel-Based Hydration Thermodynamics (ΔG_water): Evaluates water displacement energetics to determine the energetic favorability of pocket dehydration for ligand binding.
• Ligand–Residue Contact Persistence Analysis (PLIP-based): Assesses stability and persistence of ligand–residue interactions within identified pockets using PLIP-derived contact metrics.
• Cryptic Dynamic Druggability Score (CDDS): Integrates pocket lifetime, water displacement energetics, and contact persistence to produce a state-specific, interpretable druggability score.

Scientific Applications:

• KRAS G12D: Detected a metastable pocket formed by a side-chain gate absent in wild-type with favorable CDDS, ΔG_water, and selective ligand binding.
• MYC Arg58Ala: Identified a cryptic site produced by structural changes that permits binding of a designed compound with high affinity and persistent contacts.
• SRC Kinase: Revealed a cryptic site outside the active ATP pocket that is dynamically captured and bound with high affinity without perturbing the ATP site.
• TP53 Arg248Ser: Demonstrated rejection of a false-positive pocket that failed to sustain during MD simulations.
• Precision oncology and fragment hit validation: Supports rational targeting of previously inaccessible mutations and guides fragment hit validation, NMR probing, and soaking trials.

Methodology:

Long-timescale MD simulations (100–200 ns), Markov State Modeling (MSM) and TICA for state decomposition, voxel-based hydration thermodynamics (ΔG_water) analysis, PLIP-based ligand–residue contact persistence analysis, and computation of the Cryptic Dynamic Druggability Score (CDDS) integrating pocket lifetime, water displacement energetics, and contact persistence.