Evaluation of pKa Estimation Methods on 211 Druglike Compounds

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The pKa values of 211 discovery (druglike) compounds were determined experimentally using capillary electrophoresis coupled with ultraviolet spectroscopy and a novel fitting algorithm. These values were compared to those predicted by five different commercially available pKa estimation packages: ACDLabs/pKa, Marvin (ChemAxon), MoKa (Molecular Discovery), Epik (Schrodinger), and Pipeline Pilot (Accelrys). Even though the topological method MoKa was noticeably faster than ACD, the accuracy of those two methods and Marvin was statistically indistinguishable, with a root-mean-squared error of about 1 pKa unit compared to experiment. Pipeline Pilot and EpiK both produced pKa estimates in significantly worse agreement with the experiment. Interestingly, on a number of compounds, the predictions due to ACD v12 were in poorer agreement with the experiment than ACD v10. Microscopic and “apparent” pKa predictions were also compared using ACD v10. Microscopic pKas gave significantly worse agreement with the experiment than the “apparent” values. In all cases, the errors appeared to be randomly distributed across chemical series. John Manchester*, Grant Walkup, Olga Rivin and Zhiping You Infection Discovery, AstraZeneca R&D Boston. J. Chem. Inf. Model., Article ASAP DOI: 10.1021/ci100019p Publication Date (Web): March 12, 2010 Original article (at ACS)