The term pharmacophore is used to define the important features of one or more molecules having the same biological activity. Pharmacophores are selected based on several common features, such as the type of functional groups present, the distance between each atom or group of atoms and the angle between such groups or an individual atom. In this paper, we present the design and implementation of a pharmacophore searching tool, Pharmadoop, using the Hadoop framework. Due to its Hadoop implementation, Pharmadoop is a faster approach as compared to the existing standalone pharmacophore search tools. It utilizes the MapReduce algorithm to support the comparison of millions of conformers in a short time span. We further demonstrated and compared the utility of Pharmadoop on ten distinct chemical datasets of ligand molecules by running common substructure searching job on standalone and multi-system Hadoop platforms. These results were further used to perform pharmacophore searching applications on standalone and multi-node Hadoop distributions. The performance, speed and accuracy of the tool were evaluated through time-scale analysis and receiver operating curve. The Pharmadoop tool can be accessed at http://bioserver.iiita.ac.in/Pharmadoop/ .
Li Guo,Li Jiaxuan,Tian Yujia,Zhao Yunyang,Pang Xiaoyang,Yan Aixia
In this study, we built classification models using machine learning techniques to predict the bioactivity of non-covalent inhibitors of Bruton’s tyrosine kinase (BTK) and to provide interpretable and transparent explanations for these predictions. To achieve this, we gathered data on BTK inhibitors from the Reaxys and ChEMBL databases, removing compounds with covalent bonds and duplicates to obtain a dataset of 3895 inhibitors of non-covalent. These inhibitors were characterized using MACCS fingerprints and Morgan fingerprints, and four traditional machine learning algorithms (decision trees (DT), random forests (RF), support vector machines (SVM), and extreme gradient boosting (XGBoost)) were used to build 16 classification models. In addition, four deep learning models were developed using deep neural networks (DNN). The best model, Model D_4, which was built using XGBoost and MACCS fingerprints, achieved an accuracy of 94.1% and a Matthews correlation coefficient (MCC) of 0.75 on the test set. To provide interpretable explanations, we employed the SHAP method to decompose the predicted values into the contributions of each feature. We also used K-means dimensionality reduction and hierarchical clustering to visualize the clustering effects of molecular structures of the inhibitors. The results of this study were validated using crystal structures, and we found that the interaction between the BTK amino acid residue and the important features of clustered scaffold was consistent with the known properties of the complex crystal structures. Overall, our models demonstrated high predictive ability and a qualitative model can be converted to a quantitative model to some extent by SHAP, making them valuable for guiding the design of new BTK inhibitors with desired activity.
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