covalent-design

Name: covalent-design
Author: GPTomics

1.1kstars185forks

How to install covalent-design?

gptomics/bioskills/covalent-design

$npx -y skills add GPTomics/bioSkills --skill covalent-design

Installs into the current project.

Summary

Designs covalent inhibitors and warheads targeting cysteine, lysine, serine, threonine, tyrosine, and aspartate residues, with explicit handling of warhead reactivity (acrylamide, chloroacetamide, vinyl sulfone, sulfonyl fluoride, fluorosulfate, aldehyde, boronate, nitrile), reve

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SKILL.md

1	## Version Compatibility
2
3	Reference examples tested with: RDKit 2024.09+, OpenEye / AutoDock Vina 1.2+ (for covalent extensions), GOLD (commercial), DOCKovalent (web service), HCovDock 1.0+.
4
5	Before using code patterns, verify installed versions match. If versions differ:
6	- Python: `pip show rdkit` then `help(rdkit.Chem)` to check signatures
7	- CLI: check version output of each docking tool
8
9	If code throws ImportError, AttributeError, or TypeError, introspect the installed
10	package and adapt the example to match the actual API rather than retrying.
11
12	# Covalent Inhibitor Design
13
14	Design molecules that form covalent bonds with target protein residues. Clinically validated targeted covalent inhibitors include KRAS G12C inhibitors (sotorasib, adagrasib), BTK inhibitors (ibrutinib), and EGFR inhibitors (osimertinib). Covalent design requires balancing intrinsic reactivity (must form bond) vs selectivity (only the intended residue), reversibility (irreversible vs reversible covalent), and drug-likeness (warheads can hurt PK).
15
16	For warhead substructure filtering (in non-covalent contexts), see `chemoinformatics/substructure-search`. For non-covalent docking, see `chemoinformatics/virtual-screening`. For pose validation, see `chemoinformatics/pose-validation`.
17
18	## Reactive Residue Taxonomy
19
20	\| Residue \| Nucleophile \| Example compatible warheads \| Design note \|
21	\|---------\|-------------\|-----------------------------\|-------------\|
22	\| Cysteine \| Thiol / thiolate \| Acrylamide, haloacetamide, nitrile \| Commonly targeted; local pKa and geometry control reactivity \|
23	\| Lysine \| Amine \| Sulfonyl fluoride, aldehyde \| Aldehydes can form reversible imines with amines \|
24	\| Serine \| Alcohol / alkoxide \| β-lactam, boronate \| Often requires catalytic activation \|
25	\| Threonine \| Alcohol / alkoxide \| Boronate \| Context-dependent and less commonly targeted \|
26	\| Tyrosine \| Phenol / phenolate \| Sulfonyl fluoride, fluorosulfate \| Local environment strongly affects reaction \|
27	\| Aspartate/Glutamate \| Carboxylate \| Residue-specific electrophiles require experimental validation \| Do not infer aldehyde Schiff-base formation with carboxylates \|
28
29	Cysteine is frequently targeted because its thiol/thiolate can be nucleophilic and its local environment can support selective proximity-driven reaction. GSH and off-target cysteines are competing thiols, not intrinsically distinguishable from the target by the warhead alone; the complete ligand's recognition, exposure, and intrinsic reactivity determine selectivity.
30
31	## Warhead Chemistry
32
33	\| Warhead \| SMARTS pattern \| Reactivity \| Reversibility \| Cys-selective \|
34	\|---------\|----------------\|------------\|---------------\|----------------\|
35	\| Acrylamide \| `[CX3](=[OX1])([NX3])[CX3]=[CX3]` \| Moderate (Michael acceptor) \| Usually irreversible \| Often Cys-directed \|
36	\| Chloroacetamide \| `[CX3](=[OX1])([NX3])[CH2]Cl` \| High (SN2) \| Irreversible \| Often Cys-directed \|
37	\| α-haloketone \| `[CX3](=O)C[F,Cl,Br]` \| Very high \| Irreversible \| Yes (but reactive) \|
38	\| Vinyl sulfone \| `S(=O)(=O)C=C` \| Moderate (Michael) \| Irreversible \| Yes \|
39	\| Sulfonyl fluoride \| `S(=O)(=O)F` \| Moderate \| Irreversible \| Lys/Tyr/Ser \|
40	\| Fluorosulfate (SuFEx) \| `OS(=O)(=O)F` \| Moderate \| Irreversible \| Tyr/Lys \|
41	\| Aldehyde \| `[CX3H1](=O)` \| Variable \| Often reversible (covalent equilibrium) \| Context-dependent Cys/Lys/Ser chemistry \|
42	\| Boronate (B-OH or B(OH)2) \| `B(O)O` \| Moderate \| Reversible \| Ser/Thr \|
43	\| Nitrile \| `C#N` \| Low \| Reversible (Cys-S adduct) \| Cys \|
44	\| Epoxide \| `C1OC1` \| High \| Irreversible \| Cys/Lys/Asp \|
45	\| α,β-unsaturated ketone \| `[CX3](=O)C=C` \| Moderate (Michael) \| Irreversible \| Cys \|
46	\| Isothiocyanate \| `N=C=S` \| High \| Irreversible \| Cys/Lys \|
47	\| Maleimide \| `O=C1N(C(=O)C=C1)` \| Often high \| Commonly irreversible under assay conditions \| Often Cys-directed \|
48	\| Cysteine-selective heterocycle \| various \| Moderate \| Variable \| Yes (designed) \|
49
50	Practical hierarchy: Acrylamides are common attenuated electrophiles in cysteine-directed TCIs, including KRAS G12C, EGFR, and BTK programs. Haloacetamides are generally more intrinsically reactive, but actual selectivity must be measured for the complete molecule and target context.
51
52	## Decision Tree by Scenario
53
54	\| Goal \| Warhead choice \| Reactivity tier \|
55	\|------\|----------------\|-----------------\|
56	\| Cysteine TCI program \| Acrylami

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covalent-design

1.1kstars185forks

View on GitHub

How to install covalent-design?

gptomics/bioskills/covalent-design

$npx -y skills add GPTomics/bioSkills --skill covalent-design

Installs into the current project.

Summary

Files · 1

View on GitHub

SKILL.md

1	## Version Compatibility
2
3	Reference examples tested with: RDKit 2024.09+, OpenEye / AutoDock Vina 1.2+ (for covalent extensions), GOLD (commercial), DOCKovalent (web service), HCovDock 1.0+.
4
5	Before using code patterns, verify installed versions match. If versions differ:
6	- Python: `pip show rdkit` then `help(rdkit.Chem)` to check signatures
7	- CLI: check version output of each docking tool
8
9	If code throws ImportError, AttributeError, or TypeError, introspect the installed
10	package and adapt the example to match the actual API rather than retrying.
11
12	# Covalent Inhibitor Design
13
14	Design molecules that form covalent bonds with target protein residues. Clinically validated targeted covalent inhibitors include KRAS G12C inhibitors (sotorasib, adagrasib), BTK inhibitors (ibrutinib), and EGFR inhibitors (osimertinib). Covalent design requires balancing intrinsic reactivity (must form bond) vs selectivity (only the intended residue), reversibility (irreversible vs reversible covalent), and drug-likeness (warheads can hurt PK).
15
16	For warhead substructure filtering (in non-covalent contexts), see `chemoinformatics/substructure-search`. For non-covalent docking, see `chemoinformatics/virtual-screening`. For pose validation, see `chemoinformatics/pose-validation`.
17
18	## Reactive Residue Taxonomy
19
20	\| Residue \| Nucleophile \| Example compatible warheads \| Design note \|
21	\|---------\|-------------\|-----------------------------\|-------------\|
22	\| Cysteine \| Thiol / thiolate \| Acrylamide, haloacetamide, nitrile \| Commonly targeted; local pKa and geometry control reactivity \|
23	\| Lysine \| Amine \| Sulfonyl fluoride, aldehyde \| Aldehydes can form reversible imines with amines \|
24	\| Serine \| Alcohol / alkoxide \| β-lactam, boronate \| Often requires catalytic activation \|
25	\| Threonine \| Alcohol / alkoxide \| Boronate \| Context-dependent and less commonly targeted \|
26	\| Tyrosine \| Phenol / phenolate \| Sulfonyl fluoride, fluorosulfate \| Local environment strongly affects reaction \|
27	\| Aspartate/Glutamate \| Carboxylate \| Residue-specific electrophiles require experimental validation \| Do not infer aldehyde Schiff-base formation with carboxylates \|
28
29	Cysteine is frequently targeted because its thiol/thiolate can be nucleophilic and its local environment can support selective proximity-driven reaction. GSH and off-target cysteines are competing thiols, not intrinsically distinguishable from the target by the warhead alone; the complete ligand's recognition, exposure, and intrinsic reactivity determine selectivity.
30
31	## Warhead Chemistry
32
33	\| Warhead \| SMARTS pattern \| Reactivity \| Reversibility \| Cys-selective \|
34	\|---------\|----------------\|------------\|---------------\|----------------\|
35	\| Acrylamide \| `[CX3](=[OX1])([NX3])[CX3]=[CX3]` \| Moderate (Michael acceptor) \| Usually irreversible \| Often Cys-directed \|
36	\| Chloroacetamide \| `[CX3](=[OX1])([NX3])[CH2]Cl` \| High (SN2) \| Irreversible \| Often Cys-directed \|
37	\| α-haloketone \| `[CX3](=O)C[F,Cl,Br]` \| Very high \| Irreversible \| Yes (but reactive) \|
38	\| Vinyl sulfone \| `S(=O)(=O)C=C` \| Moderate (Michael) \| Irreversible \| Yes \|
39	\| Sulfonyl fluoride \| `S(=O)(=O)F` \| Moderate \| Irreversible \| Lys/Tyr/Ser \|
40	\| Fluorosulfate (SuFEx) \| `OS(=O)(=O)F` \| Moderate \| Irreversible \| Tyr/Lys \|
41	\| Aldehyde \| `[CX3H1](=O)` \| Variable \| Often reversible (covalent equilibrium) \| Context-dependent Cys/Lys/Ser chemistry \|
42	\| Boronate (B-OH or B(OH)2) \| `B(O)O` \| Moderate \| Reversible \| Ser/Thr \|
43	\| Nitrile \| `C#N` \| Low \| Reversible (Cys-S adduct) \| Cys \|
44	\| Epoxide \| `C1OC1` \| High \| Irreversible \| Cys/Lys/Asp \|
45	\| α,β-unsaturated ketone \| `[CX3](=O)C=C` \| Moderate (Michael) \| Irreversible \| Cys \|
46	\| Isothiocyanate \| `N=C=S` \| High \| Irreversible \| Cys/Lys \|
47	\| Maleimide \| `O=C1N(C(=O)C=C1)` \| Often high \| Commonly irreversible under assay conditions \| Often Cys-directed \|
48	\| Cysteine-selective heterocycle \| various \| Moderate \| Variable \| Yes (designed) \|
49
50	Practical hierarchy: Acrylamides are common attenuated electrophiles in cysteine-directed TCIs, including KRAS G12C, EGFR, and BTK programs. Haloacetamides are generally more intrinsically reactive, but actual selectivity must be measured for the complete molecule and target context.
51
52	## Decision Tree by Scenario
53
54	\| Goal \| Warhead choice \| Reactivity tier \|
55	\|------\|----------------\|-----------------\|
56	\| Cysteine TCI program \| Acrylami

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