ABSTRACT
Drug resistance is a major threat to the global health and a significant concern throughout the clinical treatment of diseases and drug development. The mutation in proteins that is related to drug binding is a common cause for adaptive drug resistance. Therefore, quantitative estimations of how mutations would affect the interaction between a drug and the target protein would be of vital significance for the drug development and the clinical practice. Computational methods that rely on molecular dynamics simulations, Rosetta protocols, as well as machine learning methods have been proven to be capable of predicting ligand affinity changes upon protein mutation. However, the severely limited sample size and heavy noise induced overfitting and generalization issues have impeded wide adoption of machine learning for studying drug resistance. In this paper, we propose a robust machine learning method, termed SPLDExtraTrees, which can accurately predict ligand binding affinity changes upon protein mutation and identify resistance-causing mutations. Especially, the proposed method ranks training data following a specific scheme that starts with easy-to-learn samples and gradually incorporates harder and diverse samples into the training, and then iterates between sample weight recalculations and model updates. In addition, we calculate additional physics-based structural features to provide the machine learning model with the valuable domain knowledge on proteins for these data-limited predictive tasks. The experiments substantiate the capability of the proposed method for predicting kinase inhibitor resistance under three scenarios and achieve predictive accuracy comparable with that of molecular dynamics and Rosetta methods with much less computational costs.
Subject(s)
Machine Learning , Proteins , Ligands , Molecular Dynamics Simulation , Mutation , Proteins/chemistryABSTRACT
<p><b>BACKGROUND</b>Cryptotanshinone (CT) is the major active constituent of Salvia miltiorrhiza Bunge. The present study was carried out to investigate the effects of CT on rats with adjuvant arthritis (AA).</p><p><b>METHODS</b>AA was induced by the metatarsal footpad injection with complete Freund's adjuvant in male Sprague-Dawley rats. The secondary inflammatory reaction was evaluated by hind paw swelling and the polyarthritis index. Activity of interleukin-1 (IL-1) was detected by the concanavalin A-induced thymocytes proliferation assay. The lymphocytes proliferation and IL-2 production were assayed by 3-(4,5-2dimethylthiazal-2yl)2,5-diphenyltetrazoliumbromide (MTT) and activated mouse splenocytes proliferation, respectively.</p><p><b>RESULTS</b>Intragastric administration of CT (50 and 100 mg/kg) significantly decreased secondary inflammatory reactions and increased the spleen and thymus index. There was a marked immunologic and inflammatory response in the AA model, which was accompanied by the decrease of thymocyte proliferation and IL-2 production as well as the increase of IL-1 production. CT apparently enhanced thymocyte proliferation and decreased IL-1 production in AA rats.</p><p><b>CONCLUSION</b>These results indicate that CT may exert its anti-inflammatory and immunoregulatory effects through inhibiting lymphocyte proliferation and production of pro-inflammatory mediators.</p>
Subject(s)
Animals , Male , Mice , Rats , Arthritis, Experimental , Drug Therapy , Allergy and Immunology , Metabolism , Cell Proliferation , Interleukin-1 , Metabolism , Interleukin-2 , Metabolism , Mice, Inbred C57BL , Phenanthrenes , Therapeutic Uses , Rats, Sprague-Dawley , Thymocytes , Cell Biology , MetabolismABSTRACT
<p><b>BACKGROUND</b>Cryptotanshinone (CT) was originally isolated from the dried roots of Salvia militorrhiza, an herb that is used extensively in Asian medicine and the extracts of this herb have been used in the treatment of several pathologies, including cardiovascular diseases, hematological abnormalities, hepatitis, and hyperlipidemia, but no studies had been carried on the treatment for rheumatic diseases with it. This study aimed to investigate the effects of cryptotanshinone on immune functions in rats with adjuvant arthritis (AA).</p><p><b>METHODS</b>Complete Freund's adjuvant was used to induce AA in rats. Thymus and spleen was aseptically taken from normal rats and the AA rats. Then a thymus lymphoid cell suspension, splenic lymphoid cell suspension and peritoneal macrophage cell suspension were prepared. After adding CT (0.1 microg/ml, 1.0 microg/ml, 10 microg/ml, 100 microg/ml, 1000 microg/ml) into the suspension, T and B lymphocytes proliferation was determined by 3-(4,5-2 dimethylthiazal-2yl)2,5-diphenyltetrazoliumbromide (MTT) assay. And the activities of interleukin-1 (IL-1) and IL-2 were measured by the mouse lymphocytes proliferation assay.</p><p><b>RESULTS</b>Thymic T and splenic B lymphocyte proliferation of the AA rat was significantly lower, and could be stored through using CT in vitro. CT (100 microg/ml and 1000 microg/ml) increased T or B lymphocytes proliferation in vitro (P < 0.01). In AA rats, the levels of IL-1 released by abdominal PMPhi significantly increased whereas the level of IL-2 released by T cells decreased in vitro. CT (1000 microg/ml) decreased the production of IL-1 and promoted production of IL-2 in vitro (P < 0.05).</p><p><b>CONCLUSIONS</b>CT can ameliorate the abnormal immunological functions in AA rats.</p>