Newer
Older
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
import itertools, pandas as pd, numpy as np, matplotlib.pyplot as plt, seaborn as sns, openbabel, openbabel.pybel, scipy, scipy.stats, openbabel.pybel
from modules import *
rule smiles_dude:
input:
smi_actives = 'resources/DHODH_DUD-E/pyrd/actives_final.ism',
smi_decoys = 'resources/DHODH_DUD-E/pyrd/decoys_final.ism',
output:
smi_actives = 'results/smiles/dude_actives.smi',
smi_decoys = 'results/smiles/dude_decoys.smi',
params:
random_source = 'resources/DHODH_DUD-E/pyrd.tar.gz',
shell: """
cp {input.smi_actives} {output.smi_actives}
shuf -n 645 --random-source={params.random_source} {input.smi_decoys} -o {output.smi_decoys}
"""
localrules: rdconf
rule rdconf:
input:
smi = 'results/smiles/{compounds_id}.smi',
output:
sdf = 'results/rdconf/{compounds_id}.sdf',
shell: """
python software/rdkit-scripts/rdconf.py --maxconfs 1 {input.smi} {output.sdf}
"""
# https://doi.org/10.1038/s41598-021-91069-7
# https://onlinelibrary.wiley.com/doi/full/10.1002/jhet.3644
# https://www.nature.com/articles/s41598-022-23006-1
# https://www.sciencedirect.com/science/article/pii/S0022286020310176
# https://www.mdpi.com/1420-3049/27/12/3660
pdb_lig = {
'1d3g': 'BRE',
'1d3h': 'A26',
'4igh': '1EA',
'6gk0': 'F1W',
'6j3c': 'B5X',
'5zf4': '9BL',
'3g0u': 'MDY',
'4oqv': '2V6',
'3u2o': '03U',
'6oc0': 'M4J',
}
localrules: pdb
rule pdb:
output:
'results/pdb/{struct_id}.pdb',
temp('results/pdb/{struct_id}_fetch.pdb'),
temp('results/pdb/{struct_id}_pdbfixer.pdb'),
temp('results/pdb/{struct_id}_pdbfixer_aligned.pdb'),
params:
delres = 'SO4,GOL,CL,ACY,ACT,LDA,ZWI,DDQ,NA,DOR',
lig = lambda wc: pdb_lig[wc.struct_id],
ref = 'resources/alphafill/AF-Q02127-F1-model_v2-FMN.pdb'
shell: """
pdb_fetch -biounit {wildcards.struct_id} | pdb_delresname -HOH > results/pdb/{wildcards.struct_id}_fetch.pdb
pdbfixer results/pdb/{wildcards.struct_id}_fetch.pdb --add-residues --add-atoms=heavy --output=results/pdb/{wildcards.struct_id}_pdbfixer.pdb
cd results/pdb
prody align ../../{params.ref} {wildcards.struct_id}_pdbfixer.pdb
cd ../..
pdb_delresname -{params.delres},{params.lig},ORO results/pdb/{wildcards.struct_id}_pdbfixer_aligned.pdb > results/pdb/{wildcards.struct_id}.pdb
pdb_selresname -{params.lig} results/pdb/{wildcards.struct_id}_pdbfixer_aligned.pdb > results/pdb/{wildcards.struct_id}_lig.pdb
"""
rule reduce:
input:
pdb = 'results/pdb/{struct_id}.pdb',
output:
pdb = 'results/pdb.reduce/{struct_id}.pdb',
fix = 'results/pdb.reduce/{struct_id}.fix.pdb',
pdbqt = 'results/pdb.reduce/{struct_id}.pdbqt',
shell: """
#export REDUCE_HET_DICT=/cluster/project/beltrao/jjaenes/software/miniconda3/envs/adfr-suite/bin/reduce_wwPDB_het_dict.txt
#conda run -p /cluster/project/beltrao/jjaenes/software/miniconda3/envs/adfr-suite reduce {input.pdb} > {output.pdb}
export REDUCE_HET_DICT=software/reduce/reduce_wwPDB_het_dict.txt
software/reduce/reduce_src/reduce -FLIP {input.pdb} > {output.pdb} || true
pdbfixer {output.pdb} --output={output.fix}
obabel {output.fix} -xr --partialcharge gasteiger -O{output.pdbqt}
"""
rule smina:
input:
sdf = 'results/rdconf/{compounds_id}.sdf',
pdb = 'results/pdb/{struct_id}.pdb',
output:
sdf = 'results/pdb.smina/{struct_id}+{compounds_id}.sdf',
threads: 64
shell: """
software/bin/smina --cpu {threads}\
--ligand {input.sdf}\
--receptor {input.pdb}\
--autobox_ligand {input.pdb}\
--out {output.sdf}\
--exhaustiveness 64\
--seed 4
"""
rule gnina:
input:
sdf = 'results/rdconf/{compounds_id}.sdf',
pdb = 'results/pdb/{struct_id}.pdb',
output:
sdf = 'results/pdb.gnina/{struct_id}+{compounds_id}.sdf',
threads: 64
shell: """
module load gcc/9.3.0; software/bin/gnina --cpu {threads}\
--ligand {input.sdf}\
--receptor {input.pdb}\
--autobox_ligand {input.pdb}\
--out {output.sdf}\
--exhaustiveness 64\
--seed 4 --no_gpu --cnn crossdock_default2018
"""
localrules: lig_decoys_plot
rule lig_decoys_plot:
input:
sdf = [ 'results/pdb.smina/{struct_id}+%s.sdf' % (compounds_id,) for compounds_id in read_dude()['compounds_id'] ],
output:
png = 'results/pdb.smina.plot_lig_decoys/{struct_id}.png',
tsv = 'results/pdb.smina.plot_lig_decoys/{struct_id}.tsv',
run:
df_ = read_dude()
df_['sdf_out'] = list(input.sdf)
df_scores_ = pd.concat([ read_affinities_dude(r.sdf_out, r.compounds_id) for i, r in df_.iterrows() ], axis=0)
fig, ax = plt.subplots(1, 2, sharey=True, figsize=(10,8))
order_ = df_scores_.query('~is_decoy').sort_values('decoyNormalisedAffinity', ascending=False)['label'].to_list()
sns.violinplot(data=df_scores_, x='minimizedAffinity', y='label', hue='is_decoy', ax=ax[0], split=True, cut=0, inner='stick', order=order_)#, color='tab:blue')
sns.barplot(data=df_scores_.query('~is_decoy'), x='decoyNormalisedAffinity', y='label', ax=ax[1], color='tab:blue', order=order_)
#ax[1].axvline(1.25, color='tab:red')
fig.savefig(output.png, bbox_inches='tight')
df_scores_.to_csv(output.tsv, sep='\t', header=True, index=False)
rule all:
"""
profile_euler/run_local --dry-run
profile_euler/run_sbatch --dry-run
"""
default_target: True
input:
#[f'results/pdb.smina/{struct_id}+dude_actives.sdf' for struct_id in pdb_lig.keys() ],
#[f'results/pdb.smina/{struct_id}+dude_decoys.sdf' for struct_id in pdb_lig.keys() ],
#[f'results/pdb.smina/{struct_id}+DHODH_ChEMBL.sdf' for struct_id in pdb_lig.keys() ],
#[f'results/pdb.smina/{struct_id}+DHODH_inhibitors.sdf' for struct_id in pdb_lig.keys() ],
#[f'results/pdb.smina/{struct_id}+DHODH_inhibitors_pubchem.sdf' for struct_id in pdb_lig.keys() ],
#[f'results/pdb.gnina/{struct_id}+dude_actives.sdf' for struct_id in pdb_lig.keys() ],
#[f'results/pdb.gnina/{struct_id}+dude_decoys.sdf' for struct_id in pdb_lig.keys() ],
#[f'results/pdb.gnina/{struct_id}+DHODH_ChEMBL.sdf' for struct_id in pdb_lig.keys() ],
#[f'results/pdb.gnina/{struct_id}+DHODH_inhibitors.sdf' for struct_id in pdb_lig.keys() ],
#[f'results/pdb.gnina/{struct_id}+DHODH_inhibitors_pubchem.sdf' for struct_id in pdb_lig.keys() ],
#expand('results/pdb.smina/{struct_id}+{compounds_id}.sdf', struct_id=pdb_lig.keys(), compounds_id=read_dude()['compounds_id']),
#expand('results/pdb.gnina/{struct_id}+{compounds_id}.sdf', struct_id=pdb_lig.keys(), compounds_id=read_dude()['compounds_id']),
expand('results/pdb.smina.plot_lig_decoys/{struct_id}.png', struct_id=pdb_lig.keys())