OpenEye FastROCS+ — 3D Shape Similarity Report vs. Gleevec

Total Hits Returned

Unique compounds after conformer collapse

0.755

Best Shape Tanimoto

Z494693834 — top 3D shape match

0.025

Lowest 2D Similarity

All hits are highly novel vs. Gleevec scaffold

Priority Follow-Up Compounds

High shape · Low 2D · IP-differentiated

Executive Summary

A 3D shape similarity search was performed using OpenEye FastROCS+ with the active bound conformation of Gleevec (Imatinib) as the query molecule. Gleevec's DFG-out inactive conformation was retrieved directly from the Mol3D field of CompoundPart record 9004727, ensuring the search probed for compounds that mimic the pharmacophoric 3D shape of Gleevec in its bioactive pose — the same geometry responsible for ABL kinase inhibition.

Key observation: All 54 returned hits display very low 2D Tanimoto similarity to Gleevec (range: 0.021 – 0.136), confirming they are structurally dissimilar at the 2D level despite overlapping well in 3D shape. This is precisely the profile sought for next-generation candidates that avoid Gleevec's intellectual property footprint while potentially retaining its binding geometry and pharmacological activity.

The top 10 compounds below were selected by maximising a Novelty Score defined as ShapeTanimoto − 2dTanimoto: a high value signals strong 3D shape complementarity to Gleevec's active conformation combined with maximum structural divergence from the competitor drug. These represent the most promising starting points for a lead optimisation campaign targeting ABL kinase with differentiated chemistry.

Shape vs. 2D Similarity — All 54 Hits

Ideal candidates cluster upper-left: high Shape Tanimoto (3D overlap), low 2D Tanimoto (structural novelty vs. Gleevec). Top-10 priority compounds are highlighted in orange. X-axis capped at 0.25 to show data spread.

Top-10 Priority Hits

Other Hits

Top 10 Priority Compounds — High Shape / Low 2D Similarity to Gleevec

Ranked by Novelty Score = ShapeTanimoto − 2dTanimoto. Higher score = better 3D mimic with greater structural novelty and IP differentiation.

#	Compound ID	Shape Tanimoto	2D Tanimoto	Novelty Score	Combo Score	Color Tanimoto	Assessment
1	Z494693834	0.7551	0.0874	0.6678	0.9601	0.2050	Best Overall
2	Z909145572	0.7119	0.0577	0.6542	0.9905	0.3241	Lowest 2D
3	Z1410908738	0.7373	0.0971	0.6402	1.0397	0.3024	High Shape
4	Z804255824	0.7127	0.0733	0.6394	0.9585	0.2458	Novel Scaffold
5	Z4743806970	0.6626	0.0297	0.6329	0.8741	0.2210	Most Novel 2D
6	Z1974291854	0.6892	0.0754	0.6138	0.9414	0.2523	High Shape
7	Z804171530	0.6815	0.0702	0.6113	0.9945	0.3131	Strong Shape
8	Z413351496	0.7241	0.1140	0.6101	1.1933	0.4692	Best Combo Score
9	Z90695798	0.6627	0.0600	0.6027	0.9500	0.2874	Strong Shape
10	Z4493815001	0.6261	0.0251	0.6010	0.8722	0.2683	Lowest 2D in Top 10

Full FastROCS+ Results — All 54 Unique Compounds

Sorted by Shape Tanimoto (descending). Top-10 priority rows highlighted.

Rank	Compound ID	Shape Tanimoto	2D Tanimoto	Novelty Score	TanimotoCombo	Color Tanimoto

Methodology & Scoring

Query structure: Gleevec (Imatinib, CAS 152459-95-5, SPO-35646) active 3D conformation retrieved from the Mol3D field of CompoundPart record 9004727 (MOL V2000, 37 atoms). The existing 3D coordinates were used directly — no new conformer generation was performed — ensuring the query reflects Gleevec's true pharmacophoric geometry in its DFG-out bound pose.

FastROCS+ scoring metrics:

Shape Tanimoto — volumetric 3D shape overlap with the query (0–1; higher = better shape match).
Color Tanimoto — electrostatic / pharmacophoric feature overlay (0–1).
TanimotoCombo — Shape + Color combined (0–2; practical threshold ≥0.8 = promising hit).
2D Tanimoto — Morgan fingerprint (ECFP4) similarity to Gleevec. Low values indicate structural novelty and IP differentiation.

Novelty Score = ShapeTanimoto − 2dTanimoto. This metric rewards high 3D shape similarity while penalising structural closeness to Gleevec, prioritising differentiated chemical space for follow-up.

OpenEye FastROCS+ · 3D Shape Similarity Report