Screening of novel inhibitors targeting lactate dehydrogenase A via four molecular docking strategies and dynamics simulations
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| 024 | 7 | 0 | |a 10.1007/s00894-015-2675-4 |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s00894-015-2675-4 | ||
| 245 | 0 | 0 | |a Screening of novel inhibitors targeting lactate dehydrogenase A via four molecular docking strategies and dynamics simulations |h [Elektronische Daten] |c [Rong Sun, Xin Li, Yuanyuan Li, Xun Zhang, Xinru Li, Xiaoyu Li, Zheng Shi, Jinku Bao] |
| 520 | 3 | |a Lactate dehydrogenase A (LDHA) is a metabolic enzyme which catalyzes the interconversion of lactate and pyruvate in the glycolysis pathway, thus playing key roles in aerobic glycolysis. The inhibition of LDHA by small molecules has become an attractive strategy for anticancer therapy in recent years. However, very few LDHA inhibitors have been reported, even though a great deal of effort has directed into identifying LDHA inhibitors using structure-based approaches. Therefore, high-throughput and high-accuracyscreeningapproaches are still urgently needed in order to target LDHA effectively. In the present work, after establishing that our docking strategies performed well using test datasets, we screened 32791 Specs products for their docking scores with the substrate-binding pocket and, separately, the cofactor-binding pocket of LDHA. We subsequently identified 76 hits (i.e., ligands that show low docking scores) for the cofactor-binding pocket and 27 hits for the substrate-binding pocket. Two representative compounds, ZINC20036549 and ZINC19369718, were then chosen for further MD simulation analysis, and we found that these compounds maintained their inhibitory activity during the MD simulations. Meanwhile, we found that ZINC19369718 interacts with a novel binding site close to the active site, and that this interaction may inhibit the catalytic activity of LDHA. Together, these results offer not only a new paradigm for identifying Specs drug-like products for novel therapeutic use but they also provide further opportunity to adopt LDHA inhibition as a strategy for cancer therapy. Graphical Abstract Four different MD simulation systems set for virtual screening to fully considered the binding modes of LDHA-ligands complexes | |
| 540 | |a Springer-Verlag Berlin Heidelberg, 2015 | ||
| 690 | 7 | |a LDHA inhibitors |2 nationallicence | |
| 690 | 7 | |a Docking strategies |2 nationallicence | |
| 690 | 7 | |a Virtual screening |2 nationallicence | |
| 690 | 7 | |a MD simulations |2 nationallicence | |
| 690 | 7 | |a Drug-like products |2 nationallicence | |
| 700 | 1 | |a Sun |D Rong |u School of Life Sciences & State Laboratory of Bio-resources and Eco-environment, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, 610065, Chengdu, China |4 aut | |
| 700 | 1 | |a Li |D Xin |u School of Life Sciences & State Laboratory of Bio-resources and Eco-environment, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, 610065, Chengdu, China |4 aut | |
| 700 | 1 | |a Li |D Yuanyuan |u School of Life Sciences & State Laboratory of Bio-resources and Eco-environment, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, 610065, Chengdu, China |4 aut | |
| 700 | 1 | |a Zhang |D Xun |u School of Life Sciences & State Laboratory of Bio-resources and Eco-environment, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, 610065, Chengdu, China |4 aut | |
| 700 | 1 | |a Li |D Xinru |u School of Life Sciences & State Laboratory of Bio-resources and Eco-environment, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, 610065, Chengdu, China |4 aut | |
| 700 | 1 | |a Li |D Xiaoyu |u School of Life Sciences & State Laboratory of Bio-resources and Eco-environment, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, 610065, Chengdu, China |4 aut | |
| 700 | 1 | |a Shi |D Zheng |u School of Medical and Nursing, Chengdu University, 610065, Chengdu, China |4 aut | |
| 700 | 1 | |a Bao |D Jinku |u School of Life Sciences & State Laboratory of Bio-resources and Eco-environment, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, 610065, Chengdu, China |4 aut | |
| 773 | 0 | |t Journal of Molecular Modeling |d Springer Berlin Heidelberg |g 21/5(2015-05-01), 1-14 |x 1610-2940 |q 21:5<1 |1 2015 |2 21 |o 894 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s00894-015-2675-4 |q text/html |z Onlinezugriff via DOI |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 900 | 7 | |a Metadata rights reserved |b Springer special CC-BY-NC licence |2 nationallicence | |
| 908 | |D 1 |a research-article |2 jats | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-springer | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1007/s00894-015-2675-4 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Sun |D Rong |u School of Life Sciences & State Laboratory of Bio-resources and Eco-environment, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, 610065, Chengdu, China |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Li |D Xin |u School of Life Sciences & State Laboratory of Bio-resources and Eco-environment, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, 610065, Chengdu, China |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Li |D Yuanyuan |u School of Life Sciences & State Laboratory of Bio-resources and Eco-environment, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, 610065, Chengdu, China |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Zhang |D Xun |u School of Life Sciences & State Laboratory of Bio-resources and Eco-environment, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, 610065, Chengdu, China |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Li |D Xinru |u School of Life Sciences & State Laboratory of Bio-resources and Eco-environment, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, 610065, Chengdu, China |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Li |D Xiaoyu |u School of Life Sciences & State Laboratory of Bio-resources and Eco-environment, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, 610065, Chengdu, China |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Shi |D Zheng |u School of Medical and Nursing, Chengdu University, 610065, Chengdu, China |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Bao |D Jinku |u School of Life Sciences & State Laboratory of Bio-resources and Eco-environment, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, 610065, Chengdu, China |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Journal of Molecular Modeling |d Springer Berlin Heidelberg |g 21/5(2015-05-01), 1-14 |x 1610-2940 |q 21:5<1 |1 2015 |2 21 |o 894 | ||