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Therefore, the research of GPCR analysis and GPCR ligand screening is the hotspot of new drug development. Accurately identifying the GPCR-drug interaction is one of the key steps for designing GPCR-targeted drugs. However, it is prohibitively expensive to experimentally ascertain the interaction of GPCR-drug pairs on a large scale. Therefore, it is of great significance to predict the interaction of GPCR-drug pairs directly from the molecular sequences. With the accumulation of known GPCR-drug interaction data, it is feasible to develop sequence-based machine learning models for query GPCR-drug pairs.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In this paper, a new sequence-based method is proposed to identify GPCR-drug interactions. For GPCRs, we use a novel bag-of-words (BoW) model to extract sequence features, which can extract more pattern information from low-order to high-order and limit the feature space dimension. For drug molecules, we use discrete Fourier transform (DFT) to extract higher-order pattern information from the original molecular fingerprints. The feature vectors of two kinds of molecules are concatenated and input into a simple prediction engine distance-weighted K-nearest-neighbor (DWKNN). This basic method is easy to be enhanced through ensemble learning. Through testing on recently constructed GPCR-drug interaction datasets, it is found that the proposed methods are better than the existing sequence-based machine learning methods in generalization ability, even an unconventional method in which the prediction performance was further improved by post-processing procedure (PPP).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The proposed methods are effective for GPCR-drug interaction prediction, and may also be potential methods for other target-drug interaction prediction, or protein-protein interaction prediction. In addition, the new proposed feature extraction method for GPCR sequences is the modified version of the traditional BoW model and may be useful to solve problems of protein classification or attribute prediction. 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