Tc-43/PDE5_Inhibitor_Designs_2H42

PDE5 Inhibitor Designs — 2H42 / GA-II

Why this target matters. PDE5 inhibitors are among the most widely prescribed drugs in the world, and the target remains actively pursued in pulmonary arterial hypertension and cardiac indications far beyond its original use.

2,090 de novo small-molecule designs docked into the catalytic pocket of human cGMP-specific phosphodiesterase 5 (PDE5A), using the sildenafil co-crystal 2H42 (PDE5 catalytic domain with sildenafil, X-ray, 2.3 Å) as the receptor.

PDE5 hydrolyses cGMP; its inhibitors (sildenafil, tadalafil, vardenafil) are established drugs for erectile dysfunction and pulmonary arterial hypertension, and the target continues to draw interest in cardiac, renal and neurodegenerative indications.

This is a score-filtered set — every design here already passed a docking-score cut, so the score range is deliberately narrow and is not a random sample of the generative run.

Contents

File	Description
designs.csv	Index of all 2,090 designs: ID, SMILES, docking score, physicochemical properties, per-design contact residues
ligands.sdf	All 2,090 docked poses as a single 3D SDF, with bond orders and formal charges from the source SMILES and coordinates from the pose
structures/	Per-design ligand-only PDB (<design_id>.pdb), 2,090 files, in the receptor frame
receptor_2H42.pdb	The single shared receptor used for every docking run

The receptor is byte-identical across all 2,090 runs, so it is stored once. Ligand poses are in the receptor's coordinate frame — load receptor_2H42.pdb together with any ligand file or SDF record, with no superposition needed.

Receptor detail. Chains A, B, C (PDE5A catalytic domain, one copy each). Docking was done in chain A, from which sildenafil was deleted; sildenafil (VIA) is still present in chains B and C, and the Zn/Mg cofactors are retained in all three. Three chain-A active-site waters were kept (HOH 75, 86, 127) and were part of the docking receptor — HOH 86 is contacted by 37% of the designs. Every design contacts chain A only.

designs.csv columns

design_id, smiles, pose_smiles, stereo_check, vina_score (kcal/mol), mw, clogp, tpsa, qed, hbd, hba, rotatable_bonds, heavy_atoms, rings, aromatic_rings, formal_charge, n_contacts, contact_residues (chain:residue, within 4 Å of the pose, ;-separated).

Rows are sorted by docking score, best first.

smiles is the structure as emitted by the generative run; pose_smiles is re-derived from the 3D coordinates of the deposited pose, so it carries the stereochemistry actually docked. See the stereochemistry note under Caveats.

Set profile

	min	median	max
AutoDock Vina score (kcal/mol)	−16.2	−13.8	−13.5
Molecular weight	373.4	423.5	496.4
cLogP	−2.3	2.3	4.0
TPSA (Ų)	72.8	111.2	136.7
QED	0.31	0.57	0.79
Heavy atoms	28	31	35
Rotatable bonds	2	4	5
Contact residues per design	9	14	19

1,869 of the 2,090 SMILES are unique; the remainder are alternative poses of a shared 2D structure (design IDs ending a/b denote poses of the same molecule). All 2,090 satisfy Lipinski's rule of five — a consequence of the upstream filter, not of the generator. 1,004 carry a net formal charge at the modelled protonation state (878 at +1, 58 at +2, 68 at −1).

The set is chemically focused rather than diverse: 1,099 distinct Murcko scaffolds, but a single benzoxazinone–pyrazolotriazine chemotype (O=C1COc2c(cccc2-c2ccn3ncnc3c2)N1) accounts for 6.4% of designs, and close relatives of it dominate the top of the score ranking.

Binding site

Residues contacted by ≥50% of the designs, with frequency:

Q817 100% · V782 100% · F820 100% · L725 99% · L765 99% · F786 99% · N661 96% · D764 77% · T723 77% · H613 76% · I665 75% · L804 60% · N662 60% · I824 56% · S663 52%

This reproduces the canonical PDE5 inhibitor pharmacophore. Q817, the invariant glutamine that makes the bidentate hydrogen bond to sildenafil's pyrimidinone, and F820, the hydrophobic-clamp phenylalanine that π-stacks against the inhibitor scaffold, are each contacted by 100% of the designs — the same two-point anchor used by all marketed PDE5 inhibitors. The hydrophobic pocket (V782, L765, L725, F786, I665, L804) is filled at ≥60%. Contacts at H613 and D764 reflect designs reaching toward the metal-binding site; a further 37% engage the conserved active-site water HOH 86. Median 14 contact residues per design.

Usage

from datasets import load_dataset

ds = load_dataset("Tc-43/PDE5_Inhibitor_Designs_2H42")["train"]
top = ds.sort("vina_score")[:10]

# 3D poses
from rdkit import Chem
mols = [m for m in Chem.SDMolSupplier("ligands.sdf") if m is not None]
mols[0].GetProp("vina_score")

# single design in its receptor
pymol receptor_2H42.pdb structures/52_2H42_II2608021409194979126914a.pdb

Caveats

Docking scores are AutoDock Vina estimates from a single rigid-receptor run against one crystal conformation. They rank poses, not affinities, and the dynamic range here is narrow (−16.2 to −13.5) because the set is already score-filtered. Poses do not model induced fit, and protonation states are as assigned by the docking preparation.

Stereochemistry. 1,699 designs carry no stereochemical assignment in their source SMILES. Of the 391 that do, the configuration read back from the docked 3D coordinates matches the declared one for 272 and differs for 119. The stereo_check column flags each row (not_declared / match / pose_differs). Where they disagree, treat pose_smiles as describing the geometry in ligands.sdf and structures/, and the declared smiles as the intended 2D identity — do not assume the deposited pose is the intended enantiomer.

Nothing in this set has been synthesised or assayed. No compound has measured PDE5 inhibition, selectivity over PDE6 or PDE11 (the basis of the visual and off-target liabilities of marketed PDE5 inhibitors), or any ADME/tox data. These are computational starting points for triage and medicinal-chemistry review, not validated inhibitors.

Citation

@misc{pde5_inhibitor_designs_2h42,
  title  = {PDE5 Inhibitor Designs (2H42 / GA-II)},
  author = {TechnetiumTx},
  year   = {2026},
  url    = {https://huggingface.co/datasets/Tc-43/PDE5_Inhibitor_Designs_2H42}
}

Receptor structure: PDB 2H42 — Crystal structure of PDE5 in complex with sildenafil.