SAR Explorer 2D: Structure-Activity Relationship & Lead Optimization

R1 — solvent-exposed vector

Faces out of the pocket; tunes physicochemical properties without touching potency.

R2 — hydrophobic pocket

A lipophilic residue lines this sub-pocket; polar groups clash here.

R3 — H-bond acceptor site

A backbone C=O waits for a ligand H-bond donor (OH, NH₂…).

R4 — H-bond donor site

A backbone N–H waits for a ligand H-bond acceptor; acids/tetrazole form a salt bridge.

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Predicted potency

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cLogP

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MW (g/mol)

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H-bond donors

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H-bond acceptors

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Metabolic stability (CYP450)

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Lipinski Rule of Five: –

How this maps to real medicinal chemistry

This is the flat 2D companion of the 3D SAR Explorer — same underlying scoring model, drawn as a schematic ligand-pocket diagram instead of a 3D docked molecule:

R2 models a hydrophobic sub-pocket — CH₃, Cl, F and CF₃ pack in well; bulky polar groups (COOH) pay a burial penalty.
R3 / R4 model complementary H-bond partners on the receptor: an acceptor residue needs a ligand donor (OH, NH₂, acids), a donor residue needs a ligand acceptor (F, OH, OCH₃, acids). Carboxylic acid and tetrazole are classic bioisosteres — similar acidity and charge, near-identical binding, different metabolism.
Metabolic stability flags groups that CYP450 enzymes attack readily: anilines (–NH₂), O-methyl ethers (–OCH₃, O-demethylation) and benzylic methyls oxidize fast; –F and –CF₃ are classic metabolic blockers.
Lipinski's Rule of Five (oral bioavailability heuristic): MW ≤ 500, cLogP ≤ 5, H-bond donors ≤ 5, H-bond acceptors ≤ 10.

Potency is a simplified score (H-bond matches + hydrophobic fit − steric/polar clash), not a real docking calculation.

Hydrophobic pocket (R2) H-bond acceptor site (R3) H-bond donor site (R4) Interaction formed