Report 3 (2022-04-29)

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) 

• Removed phenyls with ortho-substituents

• Filter: cyclic substituents with (1) zero rotatable bond (2) # rings =1 or acyclic substituents with # rotatable bonds <2

• Combined lists from Roche, Coverage, Pfizer, Bayer set: Acyclic aliphatic: 171, aliphatic rings: 94, 6-membered aromatic rings:50, 5-membered aromatic rings:28

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(4) Eliminated uninteresting substituents based on the suggestion from Industry collaborators (1. Hydrazines, 2. Halogen attached to noncarbon, 3. Pentavalent nitrogens, 4. Fluoren isotope, 5. Different halogen atoms attached to the same carbon)

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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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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

1st batch

• Using the 4-step procedure, genenerated 889 1-D torsiondrives( ) and now nearing completion

• # torsions uncovered: 46, # single bond rotations uncovered: 20

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2nd batch

• Goal: generate 1-D torsiondrives for single bond rotations (20 torsions) uncovered in 1st batch

• generate torsiondrives using the substituent list + additional substituents (see below pdf)

• 141 1-D torsiondrives selected → ready for submission

3rd batch

• Goal: generate multiple bond rotations

* negatively charged molecule

substituents

(1) [#16X2,#16X1-1,#16X3+1:1]-[#6X3:2]: t24,25,26

C(=S)([S-])-*, C(=O)([S-])-*(3.4)

(2) [*:1]~[#7X3,#7X2-1:2] : t68,69

[N-]=[N+]=[N-] [N-]C(C)C

(3) [#6X3:1]-@[#16X2,#16X1-1,#16X3+1:2]: t108