title: On the Relationship between Molecular Hit Rates in High-Throughput Screening and Molecular Descriptors.
abstract: High-throughput screening (HTS) is widely used in the pharmaceutical industry to identify novel chemical starting points for drug discovery projects. The current study focuses on the relationship between molecular hit rate in recent in-house HTS and four common molecular descriptors: lipophilicity (ClogP), size (heavy atom count, HEV), fraction of sp(3)-hybridized carbons (Fsp3), and fraction of molecular framework (f(MF)). The molecular hit rate is defined as the fraction of times the molecule has been assigned as active in the HTS campaigns where it has been screened. Beta-binomial statistical models were built to model the molecular hit rate as a function of these descriptors. The advantage of the beta-binomial statistical models is that the correlation between the descriptors is taken into account. Higher degree polynomial terms of the descriptors were also added into the beta-binomial statistic model to improve the model quality. The relative influence of different molecular descriptors on molecular hit rate has been estimated, taking into account that the descriptors are correlated to each other through applying beta-binomial statistical modeling. The results show that ClogP has the largest influence on the molecular hit rate, followed by Fsp3 and HEV. f(MF) has only a minor influence besides its correlation with the other molecular descriptors.
authors: Department of Chemistry, Umeå University, Umeå, Sweden Chemistry Innovation Center, Discovery Sciences, AstraZeneca R&D Mölndal, Mölndal, Sweden mari.hansson89@gmail.com hongming.chen@astrazeneca.com.
authors: Mari
authors: M
authors: Hansson
authors: Statistics, Discovery Sciences, AstraZeneca R&D Alderley Park, Alderley Park, UK.
authors: John
authors: J
authors: Pemberton
authors: Chemistry Innovation Center, Discovery Sciences, AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors: Ola
authors: O
authors: Engkvist
authors: Chemistry Innovation Center, Discovery Sciences, AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors: Isabella
authors: I
authors: Feierberg
authors: Chemistry Innovation Center, Discovery Sciences, AstraZeneca R&D Mölndal, Mölndal, Sweden Cygnal Bioscience, Pixbo, Sweden.
authors: Lars
authors: L
authors: Brive
authors: Statistics, Discovery Sciences, AstraZeneca R&D Alderley Park, Alderley Park, UK.
authors: Philip
authors: P
authors: Jarvis
authors: Chemistry Innovation Center, Discovery Sciences, AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors: Linda
authors: L
authors: Zander-Balderud
authors: Chemistry Innovation Center, Discovery Sciences, AstraZeneca R&D Mölndal, Mölndal, Sweden mari.hansson89@gmail.com hongming.chen@astrazeneca.com.
authors: Hongming
authors: H
authors: Chen
mesh_terms: D000465:Algorithms; D001499:Bayes Theorem; D002244:Carbon / Q000737:chemistry; D055808:Drug Discovery / Q000379:methods*; D004345:Drug Industry; D057166:High-Throughput Screening Assays / Q000379:methods*; D015233:Models, Statistical; D011336:Probability; D011381:Programming Languages; D013329:Structure-Activity Relationship; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D002244:Carbon
keywords: HTS; beta-binomial statistics; promiscuity