GQSAR for GPCR Studies

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GQSAR is a breakthrough patent pending methodology that significantly enhances the use of QSAR as an approach for new molecule design. As a predictive tool for activity, this method is significantly superior to conventional 3D and 2D QSAR. Here we explain application of GQSAR for optimizing GPCR compounds in non congeneric series.

Technology

Fragment Based-GQSAR for GPCR Studies Presenter: Kundan B. Ingale Application Scientist kundani@vlifesciences.com

[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],GPCR…

Challenges in Multi-target ligand design for GPCRs ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Key elements of GQSAR ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Group QSAR: For lead optimization ,[object Object],[object Object],[object Object],Fig: GQSAR Workflow

10/10/11 Dataset for GQSAR ,[object Object],[object Object],Class Number of molecules Activity (Ki nM) Min Max C1 (Piperidine) 69 HT1A 0.91 3200.00 HTT 0.24 9006.00 C2 (Piperazine) 56 HT1A 0.12 475.00 HTT 1.30 3900.00 C3 (non ring N atom) 26 HT1A 2.00 1470.00 HTT 0.50 4700.00 C4 ( 1,2,3,6-tetrahydropyridine) 8 HT1A 10.90 92.60 HTT 19.80 387.00 C5 ( azabicyclo[3.2.1]oct-3-ene) 3 HT1A 127.70 357.00 HTT 8.50 33.00

10/10/11 Representative Molecules Piperazine (C2) Non Ring Nitrogen (C3) 1,2,3,6-tetrahydropyridine (C4) azabicyclo[3.2.1]oct-3-ene (C5) Piperidine (C1)

Fragmentation Pattern Fragment R1 (aromatic region): aromatic ring connected with the core of the molecule i.e. fragment R2 Fragment R2 (anchor region): substituent present in the center of the molecule Fragment R3 (flexible region): substituent connected to other end of the fragment R2

Relationship between 5HT1A and 5HTT inhibition Design and optimize molecules for multi-target activity r2 = 0.051 Fig: Scatter Plot of pKi_5HT1A Vs pKi_5HTT

Data Processing and Model building ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

10/10/11 GQSAR Model ,[object Object],[object Object],[object Object],[object Object],[object Object],Fig: Contribution Plot for descriptors in GQSAR equation

Model Validation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

[object Object],[object Object],[object Object],[object Object],[object Object],10/10/11 Model Interpretation * Figures in bracket indicate contribution of descriptor towards 5HTT and 5HT1A respectively ↑ Branched substitution ↑ Polar surface ↓ Branched Substitution ↓ H-don N atom attached to 2 heavy atoms pKi (5HTT): -0.97; pKi(5HT1A) : 0.04

$10/10/11 10/10/11 ,[object Object],[object Object],[object Object],Model Interpretation (Interaction Descriptors) * Figures in bracket indicate contribution of descriptor towards 5HTT and 5HT1A respectively pKi (5HTT): -0.59; pKi(5HT1A) : -0.3 ↓ sp2 atoms separated by 2 bonds ↓ Branched substitution ↓ sp2 atoms separated by 6 bonds ↓ Molar refractivity$

10/10/11 Summary and Conclusion ,[object Object],[object Object],[object Object],[object Object],10/10/11

References ,[object Object],[object Object],[object Object],[object Object],[object Object]

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GQSAR for GPCR Studies

1. Fragment Based-GQSAR for GPCR Studies Presenter: Kundan B. Ingale Application Scientist kundani@vlifesciences.com

6. 10/10/11 Representative Molecules Piperazine (C2) Non Ring Nitrogen (C3) 1,2,3,6-tetrahydropyridine (C4) azabicyclo[3.2.1]oct-3-ene (C5) Piperidine (C1)

7. Fragmentation Pattern Fragment R1 (aromatic region): aromatic ring connected with the core of the molecule i.e. fragment R2 Fragment R2 (anchor region): substituent present in the center of the molecule Fragment R3 (flexible region): substituent connected to other end of the fragment R2

8. Relationship between 5HT1A and 5HTT inhibition Design and optimize molecules for multi-target activity r2 = 0.051 Fig: Scatter Plot of pKi_5HT1A Vs pKi_5HTT

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11. Model Representation

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Editor's Notes

4pathClusterCount^2 (-1.47, -1.11): Substituent with branched structure PSAExclPandS (2.62, 2.92): Substituent with polar surface area. Substituent with sp3 hybridized nitrogen atom substituted with two heavy atoms
R3-4pathClusterCount*R1-T==2: R3 substituent with branched substituents along with presence of sp2 hybridized atoms separated with two topological bond distance at R1 R3-smr*R1-T==6: R3 Substituent`s molar refractivity (i.e. bulk) along with presence of sp2 hybridized atoms separated with six topological bond distance at R1 R3-chi3Cluster*R1-T=C1: R3 substituent`s chi3cluster topological index along with presence of sp2 hybridized carbon atom counts at R1 R3-SsCH3count*R1-TCF5 : R3 substituent with sp3 hybridized carbon atom attached to one heavy atom along with presence of F atom separated from C by five topological bond distance at R1

GQSAR for GPCR Studies

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Editor's Notes