About the eNTRy Rules
Entryway classifies molecules that are likely capable of accumulating in Gram-negative bacteria. Entryway calculates physiochemical properties of molecules and compares to a training set of compounds. Please cite: Richter, Drown, Riley, Garcia, Shirai, Svec, Hergenrother. Nature 545, 299–304 (2017).
We have found that the presence of suitable ionizable nitrogen on a small molecule greatly improves the likelihood that a molecule will accumulate in bacteria. This phenomenon is most reliable with primary amines. While the presence of an ionizable nitrogen seems to be necessary for accumulation, it is not sufficient. Proper shape and flexibility are also necessary.
Flat molecules are more likely to accumulate. While there are several metrics for describing a molecule's three-dimensionality, we have found that globularity is most successful in discriminating accumulators and non-accumulators. In the initial report of the eNTRy rules, we used MOE to calculate globularity. Entryway uses an open-source method. Globularity values calculated by entryway may differ slightly from those made by MOE.
Flexible compounds are less likely to accumulate. We have found the number of rotatable bonds to be a suitable surrogate for flexibility. Entryway defines rotatable bonds as non-terminal single bonds between heavy atoms not in a ring. N-C bonds in amides are not counted as rotatable.
The localized polarity and steric effects near the amine are important considerations when implementing the eNTRy rules as these factors are not explicitly included in the Entryway results. Previously, it was found that increase amphiphilic moment (measured as vsurf_A) correlated with increased accumulation while steric encumbrance correlated negatively with accumulation.