Entryway analysis

The eNTRy rules are a series of guidelines that can increase small-molecule accumulation in gram-negative bacteria. A molecule is likely to accumulate if it contains few rotatable bonds, low three dimensionality, and an ionizable nitrogen.

The webapp entry-way was created to aid in the application of these guidelines by performing the necessary predictions of physiochemical properties. Although freely available at entry-way.org, these same calculations can be performed locally.

Installing the pakage

Entryway relies on OpenBabel and RDKit for handling chemical structures and conformer generation and NumPy for globularity calculations. These dependencies are most conveniently installed via Conda. The included environment.yml file makes this straightforward:

# Download source
git clone https://github.com/aethertier/entry-cli.git
cd entry-cli

# Prepare conda environment
conda env create -f environment.yml
conda activate entry-cli-env

# Install module 'entry_cli'
make install
# To uninstall the package later, run 'make uninstall'

Running calculations

Although other file formats will be implemented shortly, molecules can be submitted as SMILES strings for now. This can be achieved through command line arguments:

# Ampicillin
entry-cli -s "O=C(O)[C@@H]2N3C(=O)[C@@H](NC(=O)[C@@H](c1ccccc1)N)[C@H]3SC2(C)C"

# Deoxynybomycin
entry-cli -s "CC(C1=CC(C(C)=CC(N2C)=O)=C2C3=C1N4CO3)=CC4=O"

Alternatively, a batch file can be provided that contains several molecules with SMILES and names. Results are reported as a csv file. The name of the output file is optional. If no output file is specified, then the base name of the batch file is used:

# The following will provide the same result
entry-cli -b tests/b-lactams.smi -o tests/b-lactam.csv
entry-cli -b tests/b-lactams.smi

Additional commnd line commands can be shown using the --help option:

usage: entry-cli [-h] [-s SMILES string | -b Batch file] [-o Output file]
                 [--conf-cutoff <int>] [--rmsd-cutoff <int>]
                 [--energy-cutoff <int>]

Performs calculation of physiochemical properties of potential antibiotics.
SMILES strings are parsed, conformers are generated, and properties
calculated. Properties include: chemical formula, molecular weight, rotatable
bonds, globularity, and PBF.

optional arguments:
  -h, --help            show this help message and exit

Input & Output Options:
  -s SMILES string, --smiles SMILES string
  -b Batch file, --batch Batch file
  -o Output file, --output Output file
                        Defaults to csv file with same name as input

Conformer Generation Options:
  --conf-cutoff <int>   Max number of conformers to generate, default: 100,000
  --rmsd-cutoff <int>   Similarity threshold for conformers, default: 0.5
  --energy-cutoff <int>
                        Max relative energy between conformers, default: 50

Alternatively, the functions can be imported as a python module.

from entry_cli.calc_props import smiles_to_ob, average_properties

Citing

Please cite our paper on the eNTRy rules:

Richter, M. F.; Drown, B. S.; Riley, A. P.; Garcia, A.; Shirai, T.; Svec, R. L.; Hergenrother, P. J. Nature 2017, 545, 299-304.