physical_property

The SAMPL7 physical property challenge (now closed to submissions)

We are excited to announce a new set of SAMPL7 challenges focusing on pK_a, partitioning, and permeability. The Ballatore group at UCSD is contributing a set of measured water-octanol log P, log D, and pK_a values for 22 compounds. They also provided Parallel Artificial Membrane Permeability Assay (PAMPA) permeability and melting point values they measured.

pK_a prediction will consist of predicting relative free energies between compound microstates (which could be also thought of as the reaction free energy for that particular microstate transition; see pK_a instructions). We choose free energies rather than pK_a values given the recent work of Gunner et al.. For the purposes of the pK_a challenge all possible tautomers of each ionization (charge) state are defined as distinct protonation microstates. Macro pK_a values may be submitted to allow for a consistency check.

The partitioning prediction challenge will focus on predicting the difference in free energy for the neutral form between water and octanol. As a part of post prediction analysis challenge oraginzers will combine participant-predicted pK_a and log P values to obtain estimated distribution coefficients, which will also be compared against experimental values. Participants may optionally submit their own log D values for a consistency check.

A PAMPA permeability prediction challenge will also be run in parallel to the pK_a and partition coefficient challenge.

All three challenges are optional, so participants may participate in all or any combination of these challenges.

Additionally, there’s the opportunity to predict melting points. Please let us know if you are interested in this.

Please sign up for our e-mail list for announcements of any changes (be sure to indicate interest in SAMPL7 physical properties). Be sure to also “watch” this GitHub repository.

Challenge timing details

Submissions to the SAMPL7 physical property challenge will be due October 8, 2020. Challenge participants will have the option of predicting relative free energies between microstates to determine pK_a¹, and/or the difference in free energy of the neutral molecules between water and octanol to determine partition coefficients, and/or the log_Papp to determine permeabilities of 22 compounds.

Submission details, templates, instructions and analysis are linked to in the manifest.

The submission servers are now live: SAMPL7 pK_a submissions and SAMPL7 logP/permeability submissions. Note that each challenge component has its own format, but logP and permeability share the same submission URL.

A view of the compounds

Fig 1. SAMPL7 Challenge molecules. Log of the partition coefficient between n-octanol and water was determined via potentiometric titrations using a Sirius T3 instrument. pK_a values were determined by potentiometric titrations using a Sirius T3 instrument. Log of the distribution coefficient between n-octanol and aqueous buffer at pH 7.4 were determined via potentiometric titrations using a Sirius T3 instrument, except for compounds SM27, SM28, SM30-SM34, SM36-SM39 which had log D_7.4 values determined via shake-flask assay. PAMPA assay data includes effective permeability, membrane retention, and log of the apparent permeability coefficient. Permeabilities for compounds SM33, SM35, and SM39 were not determined. Compounds SM35, SM36 and SM37 are enantiopure and have a chiral center. All other compounds are not chiral.

Experimental details

Compounds were synthesized by the Ballatore Lab at UC San Diego in 1-6 steps and were >95% pure as indicated by NMR and LCMS. pK_a measurements were obtained via automated potentiometric titrations using a Sirius T3 instrument (Pion, Inc). Three titrations were performed from pH 1.8 to pH 12.2 using ionic strength adjusted water (0.15 M KCl), acid (0.5 M HCl, 0.15 M KCl) and base (0.5 M KOH, 0.15 M KCl). The pK_as of select compounds (Compounds SM30 and SM39) with low aqueous solubility were measured using a cosolvent protocol; Yasuda-Shedlovsky extrapolation method was used to estimate the pK_a at 0% cosolvent.

Log P measurements of compounds with known experimental pK_a were obtained via potentiometric titrations using a Sirius T3 instrument. Log D_7.4 values were extrapolated from the measured log P. Compounds with pK_a > 10 had log D_7.4 measured via shake-flask method (shake-flask log D_7.4 carried out by Analyza, Inc).

Melting points of the crystalline material were taken using Mel-Temp II (Barnstead Thermolyne). Crystals were grown by slow evaporation in a single solvent (dichloromethane) or by vapor diffusion (hexanes/dichloromethane or dichloromethane/methanol). Intrinsic solubilities were obtained using the experimental log P and the melting point via Yalkowski intrinsic solubility equation (log S = –log P – 0.01 ´ (mp – 25) + 0.5).

Effective permeability (log_Papp) was measured by PAMPA using the Corning GentestTM pre-coated PAMPA plate system with quantitation by HPLC-UV (experiments carried out by Analyza, Inc).

What's here

• SAMPL7_molecule_ID_and_SMILES.csv: A .CSV file containing SAMPL7 challenge molecule IDs and SMILES. SMILES were provided by the Ballatore lab.
• logP/: This folder contains participant submissions, instructions, a submission template and the analysis for the log P challenge. Also contains an input file in .CSV format with SMILES strings of the neutral states of the molecules.
• pKa: This folder contains instructions, a submission template and the analysis for the pK_a challenge. Also contains challenge input files in .CSV format with SMILES of enumerated microstates and both .MOL2 and .SDF files of each microstate. This folder contains instructions and a submission template for the pK_a challenge. Microstates (tautomers and protomers) were generated with a notebook wich uses RDKit and OpenEye tools. Additional microstates were enumerated using Chemicalize (Chemaxon) and Epik (Schrodinger) and added to the notebook generated .CSV files.
• permeability/: Folder contains input files in .CSV format with SMILES strings of molecules. This folder contains instructions, a submission template and the analysis for the permeability challenge.
• images/: Folder containing images related to this challenge in PDF and/or JPEG format.
• experimental_data/: Folder contains experimental measurements of pK_a, partitioning, and permeability values.

Publication on experimental measurements

Karol R. Francisco, Thomas J. Paniak, Marisa C. Kozlowski, and Carlo Ballatore. "Structure Property Relationships of N-Acylsulfonamides and Related Bioisosteres". European Journal of Medicinal Chemistry. 2021 March. https://doi.org/10.1016/j.ejmech.2021.113399

This was updated later with a corrigendum with updated values for compounds 27 and 29 which are reflected here as of Oct. 20, 2021.