In Silico Target Predictions: Defining a Benchmarking Data Set and Comparison of Performance of the Multiclass Naïve Bayes and Parzen-Rosenblatt Window

Abstract

In this study, two probabilistic machine-learning algorithms were compared for in silico target prediction of bioactive molecules, namely the well-established Laplacian-modified Naïve Bayes classifier (NB) and the more recently introduced (to Cheminformatics) Parzen-Rosenblatt Window. Both classifiers were trained in conjunction with circular fingerprints on a large data set of bioactive compounds extracted from ChEMBL, covering 894 human protein targets with more than 155,000 ligand-protein pairs. This data set is also provided as a benchmark data set for future target prediction methods due to its size as well as the number of bioactivity classes it contains. In addition to evaluating the methods, different performance measures were explored. This is not as straightforward as in binary classification settings, due to the number of classes, the possibility of multiple class memberships, and the need to translate model scores into "yes/no" predictions for assessing model performance. Both algorithms achieved a recall of correct targets that exceeds 80% in the top 1% of predictions. Performance depends significantly on the underlying diversity and size of a given class of bioactive compounds, with small classes and low structural similarity affecting both algorithms to different degrees. When tested on an external test set extracted from WOMBAT covering more than 500 targets by excluding all compounds with Tanimoto similarity above 0.8 to compounds from the ChEMBL data set, the current methodologies achieved a recall of 63.3% and 66.6% among the top 1% for Naïve Bayes and Parzen-Rosenblatt Window, respectively. While those numbers seem to indicate lower performance, they are also more realistic for settings where protein targets need to be established for novel chemical substances.

Development of a Novel Azaspirane That Targets the Janus Kinase-Signal Transducer and Activator of Transcription (STAT) Pathway in Hepatocellular Carcinoma in Vitro and in Vivo

“…In this regard, we applied the well established Laplacianmodified naive Bayesian classifier as implemented by Koutsoukas et al (44) and predicted potential targets of CIMO. It was found that membrane-associated phospholipase A2, histamine H2 receptor, proteinase-activated receptor 1, steroid hormone receptor ERR1, gonadotrophin-releasing hormone receptor, and prostaglandin E synthase had a normalized likelihood of 10.41, 4.98, 4.96, 4.43, 4.04, and 4.04 for CIMO, respectively.…”

Synthesis of 1,2-benzisoxazole tethered 1,2,3-triazoles that exhibit anticancer activity in acute myeloid leukemia cell lines by inhibiting histone deacetylases, and inducing p21 and tubulin acetylation

“…44 We identified potential targets based on classspecific cut-offs and found different members the family of histone deacetylases (HDACs)…”

Nano-MoO3-mediated synthesis of bioactive thiazolidin-4-ones acting as anti-bacterial agents and their mode-of-action analysis using in silico target prediction, docking and similarity searching

“…23 The predicted target, potassium voltage-gated channel subfamily A member 5, with a corresponding probability value of 0.069, is shown in Table 5. In addition, the occurrence of potassium voltage-gated channel subfamily A member 5 in the background dataset was measured.…”