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Quantitative Structure-Activity Relationship Study for HIV-1 LEDGF/p75 inhibitors

Author(s):

Yang Li, Yujia Tian, Yao Xi, Zijian Qin and Aixia Yan*   Pages 1 - 13 ( 13 )

Abstract:


Background: HIV-1 Integrase (IN) is an important target for the development of the new anti-AIDS drugs. HIV-1 LEDGF/p75 inhibitors, which block the integrase and LEDGF/p75 interaction, have been validated for reduction in HIV-1 viral replicative capacity.

Methods: In this work, computational Quantitative Structure-Activity Relationship (QSAR) models were developed for predicting the bioactivity of HIV-1 integrase LEDGF/p75 inhibitors. We collected 190 inhibitors and their bioactivities in this study and divided the inhibitors into nine scaffolds by the method of T-distributed Stochastic Neighbor Embedding (TSNE). These 190 inhibitors were split into a training set and a test set according to the result of a Kohonen’s self-organizing map (SOM) or randomly. Multiple Linear Regression (MLR) models, support vector machine (SVM) models and two consensus models were built based on the training sets by 20 selected CORINA Symphony descriptors.

Results: All the models showed a good prediction of pIC50. The correlation coefficients of all the models were more than 0.7 on the test set. For the training set of consensus Model C1, which performed better than other models, the correlation coefficient(r) achieved 0.909 on the training set, and 0.804 on the test set.

Conclusion: The selected molecular descriptors show that hydrogen bond acceptor, atom charges and electronegativities (especially π atom) were important in predicting the activity of HIV-1 integrase LEDGF/p75-IN inhibitors.

Keywords:

HIV-1 integrase LEDGF/p75 inhibitor, Chemical scaffold, Quantitative structure–activity relationship (QSAR) model, Molecular descriptor

Affiliation:

Institute of Science and Technology, Shandong University of Traditional Chinese Medicine, Ji`nan, Shandong , 250355, P. R., State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, P.O. Box 53, Beijing University of Chemical Technology, 15 Bei San Huan East Road, Beijing 100029, P. R., State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, P.O. Box 53, Beijing University of Chemical Technology, 15 Bei San Huan East Road, Beijing 100029, P. R., State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, P.O. Box 53, Beijing University of Chemical Technology, 15 Bei San Huan East Road, Beijing 100029, P. R., State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, P.O. Box 53, Beijing University of Chemical Technology, 15 Bei San Huan East Road, Beijing 100029, P. R.



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