Case study
Discovery of a Cryptic Pocket in Aminergic GPCRs - A Collaborative effort by Acellera and Pfizer
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In the arena of drug discovery, G-protein coupled receptors (GPCRs) command significant interest due to their crucial role in cellular signal transduction and their potential as therapeutic targets. Approximately 34% of all marketed drugs target GPCRs. This case study delves into the collaborative efforts of Acellera and Pfizer in revealing a hidden binding pocket in Dopamine D3 receptors (D3R), a subset of the aminergic GPCR family, using advanced simulation technologies.


D3Rs have been a focal point in the study of drug addiction, with several selective D3R antagonists reported in literature. A recent breakthrough involves PF-4363467, a D3R dual antagonist with unique binding properties and therapeutic effects. Traditional methods, however, struggled to accurately predict its binding mode. This challenge laid the groundwork for a deeper investigation using molecular dynamics (MD) simulations.

Collaborative Methodology

Acellera and Pfizer embarked on a comparative study of PF-4363467 with other well-characterized D3R antagonists. The approach combined point mutation studies with large-scale MD simulations, a technique increasingly used to capture the dynamic nature of protein-ligand interactions.

Key Findings

  1. Unique Binding Mode of PF-4363467: MD simulations uncovered a distinct binding mode for PF-4363467, different from those predicted by rigid docking methods. This finding was instrumental in understanding the compound's high affinity for D3R.
  2. Discovery of a Cryptic Pocket: Remarkably, the study revealed a previously unknown binding pocket in the D3R, formed by the displacement of specific residues. This pocket is now recognized as a potential target for designing novel D3R antagonists.
  3. Implications for Drug Design: The discovery of the cryptic pocket in D3Rs opens new avenues in the design of GPCR-targeted drugs. It underscores the importance of considering receptor flexibility and the dynamic nature of ligand binding in drug design.


This collaboration between Acellera and Pfizer exemplifies the power of combining cutting-edge computational methods with traditional pharmacological approaches. The discovery of the cryptic pocket in D3Rs not only enhances our understanding of GPCR biology but also paves the way for the development of new therapeutics targeting aminergic GPCRs. This case study serves as a testament to the potential of collaborative innovation in advancing the frontiers of drug discovery.

About Acellera and Pfizer

Acellera, a pioneer in applying GPU technology for molecular dynamics, brings computational expertise in drug discovery. Pfizer, with its extensive experience in pharmaceutical development, complements this expertise, making this partnership a beacon of innovation in the field of drug discovery.