pK_a measurements for the SAMPL6 prediction challenge for a set of kinase inhibitor-like fragments

Abstract

we used UV absorbance-based pK a measurements to construct a high-quality experimental reference dataset 36 of macroscopic pK a s for the evaluation of computational pK a prediction methodologies that was utilized in CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint (which . http://dx.doi.org/10.1101/368787 doi: bioRxiv preprint first posted online Jul. 13, 2018;

SAMPL6 challenge results from $$pK_a$$ predictions based on a general Gaussian process model

“…Macroscopic pK a s are then analytically calculated from a combination of microscopic transitions (Section 2.4). We used our model to predict microscopic (type I) and macroscopic (type III) pK a s for 24 drug like molecules in the SAMPL6 blind challenge [13]. The SAMPL6 submission IDs assigned to our predictions where 6tvf8 (type I) and hytjn (type III).…”

“…The SAMPL6 organizers initially provided an approximate evaluation of predicted microscopic transitions using macroscopic pK a s. Organizers provided experimental macroscopic pK a s for all molecules, but experiments for microscopic pK a s were only performed for seven molecules [10]. In an attempt to provide feedback on type I predictions, organizers compared experimental data for molecules with only one experimental pK a or two pK a s with a difference greater than 3 relative to microscopic predictions.…”

“…Experimental macroscopic pK a s were collected for 24 drug like molecules using an established spectrophotometric technique limited to a pH range between two and twelve. As a part of follow up analysis, a few NMR experiments were performed to determine the microscopic pK a s of a select few molecules [10]. Microscopic pK a s refer to an equilibrium resulting from removing a specific hydrogen from a molecule and macroscopic pK a s describe the process of removing any hydrogen or an overall change in charge state [11,12].…”

“…For each type of submission participants were encouraged, but not required, to submit all predictions their model generated for every molecule. SAMPL6 organizers then evaluated predictions based on experimental results for all macroscopic and a select set of microscopic pK a s [13]. Details for the challenge including experimental results, all submitted predictions, and an overview analysis are available online (github.com/MobleyLab/SAMPL6).…”

An explicit-solvent hybrid QM and MM approach for predicting pKa of small molecules in SAMPL6 challenge

“…For further details, please refer Isik et. al [38] where the organizers have described the rationale for choosing the molecules as well as the methods used for experimental pKa prediction.…”