Step 1. Generation of a list of small and rigid substituents.
(1) For each molecule from an input molecule set(Roche, Coverage, Pfizer Discrepancy and Bayer set), using scaffolds, identified substituents; (2) Listed up all substituents; (3) Eliminated complex substituents (by checking number of rotatable bonds, number of rings)
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Step 2. Generation of small molecules.
Instead of enumerating molecule by adding substituents to a scaffold, molecules were generated by combining two substituents. The bond formed during each combination becomes a center bond, which will be rotated during its torsion scan;
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([1*])c1ccccc1 + [*:1]Nc1ccccc1 → c1cc[c:1](cc1)[NH:2]c2ccccc2
Step 3. Elimination of internal hydrogen bond forming molecules.
Generated conformers for each molecule and found and excluded molecules having internal hydrogen bond forming conformers using MDTraj.
Step4. List molecules matching to each torsion parameter and select torsions.
(1) Listed molecules matching to each torsion parameter; (2) Clustered each list into around 10 clusters using DBSCAN and MACCS keys; (3) Chose center molecule from each cluster
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