3-Point Pharmacophore Triangles → 10K Bits
Each pharmacophore is a triangle of 3 features with specific distances:
7 Pharmacophore Types: A (acceptor), D (donor), N (negative), P (positive), H (hydrophobic), R (aromatic), X (other)
6 Distance Ranges: 2.0-4.5, 4.5-7.0, 7.0-10.0, 10.0-14.0, 14.0-19.0, 19.0-24.0 Å
~10,549 possible triangular pharmacophores → Each gets 1 bit → 10K bit fingerprint
Original Pharmprint
Many conformers
C1
C2
C3
C4
Individual 10K bit fingerprints
C1:
... (10K bits)
C2:
... (10K bits)
C3:
... (10K bits)
C4:
... (10K bits)
All conformer shapes superposed:
OR ALL BITS
Combined 10K bit fingerprint
... (10K bits)
Problem: Cannot identify which conformer matched
Polypharmprint Method
Hundreds of conformers
C1
C2
C3
C4
Keep each 10K bit fingerprint separate
Individual conformer shapes (kept separate):
Individual 10K bit fingerprints (kept separate)
C1:
... (10K bits)
C2:
... (10K bits)
C3:
... (10K bits)
C4:
... (10K bits)
Advantage: Can trace back to exact conformer that matched
Polypharmprint Matching Process
Query Molecule
C1
...
C2
...
C3
...
C4
...
BEST MATCH
Hit Molecule
C1
...
C2
...
C3
...
C4
...
Key Breakthrough:
We can access the exact starting 3D conformation of the matching conformer pharmprint, enabling dramatically more efficient exploration of the conformational space when aligning query and hit molecules. This transforms molecular alignment from a computationally expensive global search into a targeted, efficient process.
References
Original PharmPrint Method:
- McGregor, M. J., & Muskal, S. M. (1999). Pharmacophore fingerprinting. 1. Application to QSAR and focused library design. J. Chem. Inf. Comput. Sci., 39(3), 569-574. [PDF]
- McGregor, M. J., & Muskal, S. M. (2000). Pharmacophore fingerprinting. 2. Application to primary library design. J. Chem. Inf. Comput. Sci., 40(1), 117-125. [PDF]