Volume 1 Preface xiii 1 Metalloenzyme Informatics and Drug Design 1 Jun-Lin Yu, Xiao-Tian Huang, Dao-Xing Chen, Cong Zhou, Yao-Gen Wang, and Guo-Bo Li 1.1 Introduction 1 1.2 Metalloenzyme Informatics 2 1.3 Computational Tools for Metalloenzyme Drug Design 13 1.4 Metalloenzyme-Disease Association 18 1.5 Concluding Remarks 20 2 Metal-Binding Pharmacophores in Metalloenzyme Drug Discovery 25 Lilia M. Baldauf, Emily A. Podd, and Seth M.

Cohen 2.1 Introduction 25 2.2 MBP Databases and MBP Trends 27 2.3 Recent Advancements in MBP Development 34 2.4 Metal-Binding Isosteres (MBIs) 41 3 Modeling Metalloenzyme Catalytic Mechanisms by QM/MM Calculations 61 Zhe Li and Ruibo Wu 3.1 Introduction 61 3.2 The QM/MM Method 63 3.3 Application of the QM/MM Methods in Metalloenzymes 80 3.

4 Summary 106 4 Experimental Strategies in Metalloenzyme Mechanism Study and Drug Discovery 119 Si-Qi Wei, Zi-Yang Chen, and Guo-Bo Li 4.1 Introduction 119 4.2 Metalloenzyme Catalysis Mechanism 120 4.3 Metalloenzyme Inhibition Mechanism 127 4.4 Metalloenzyme Inhibitor Selectivity by Thermal Proteome Profiling 142 4.5 Concluding Remarks 146 5 Targeting Metalloenzymes by Metallo-Drugs 151 Cheng Chen, Kewu Yang, Hongyan Li, and Hongzhe Sun 5.1 Introduction 151 5.2 Mechanisms of Bacterial Resistance Mediated by Metalloenzymes 153 5.

3 Metallo-drugs/Metallo-agents: Targeting Metalloenzymes Against Superbugs 156 5.4 Conclusion and Perspectives 164 6 Targeting Metallo-Β-Lactamases to Combat Antibiotic Resistance 171 Mitchell A. Jeffs, Montserrat Mora-Ochomogo, Laila Masalha, Dylan W. Zhao, and Christopher T. Lohans 6.1 Introduction 171 6.2 Metallo-β-Lactamase Structure and Evolution 174 6.3 Clinical Impact of MBLs 177 6.

4 Recent Advances in the Development of Therapeutics to Target MBL-Producing Pathogens 182 6.5 Concluding Remarks 192 7 Targeting Disease-Linked Metalloenzymes Involved in RNA Metabolism 213 Simranjeet Kaur and Wei Shen Aik 7.1 Background 213 7.2 Fe(II) and 2-Oxoglutarate-Dependent Oxygenases Involved in Epitransciptomic Regulation of RNA Metabolism 214 7.3 Fat Mass and Obesity Associated Protein (FTO) 214 7.4 Generic 2OG Mimetic Inhibitors, Metal Ion Chelators 219 7.5 Endogenous TCA Metabolites as Inhibitors 220 7.6 High Throughput Virtual Screening for Inhibitor Development 221 7.

7 Structure-Based Rational Inhibitor Design 224 7.8 Benzene-1,3-Diol Derivatives 230 7.9 AlkB Human Homologue 5 (ALKBH5) 231 7.10 ALKBH5 Inhibition 234 7.11 AlkB Human Homologue 3 (ALKBH3) 247 7.12 Zn2+-Dependent RNA Editing Enzymes 249 7.13 Crystal Structure of Human CPSF73 256 7.14 Active Site Architecture 256 7.

15 Assembly of the 3' Processing Machinery Activates the CPSF73 Endonuclease 257 7.16 CPSF73 Inhibition in Cancer 258 7.17 CPSF73 Inhibition in Parasitic Infections 259 7.18 Conclusion and Perspectives 260 8 Cyclic Nucleotide Phosphodiesterases: Important Therapeutic Targets 269 Deyan Wu, Shuheng Huang, and Hai-Bin Luo 8.1 Introduction 269 8.2 Phosphodiesterases (PDEs) 269 8.3 PDEs Inhibitor Discovery 273 8.4 Concluding Remarks and Future Perspectives 284 9 HDAC: A Rising Star in Cancer Therapy 291 Tao Liang, Hao Fang, and Xuben Hou 9.

1 Introduction 291 9.2 HDACs 291 9.3 The Roles of HDACs in Cancer 299 9.4 HDAC Inhibitors 303 9.5 The Trends of Next-Generation HDAC Inhibitors 308 9.6 Concluding Remarks and Future Perspectives 313 Glossary 314 References 315 Volume 2 Preface xiii 10 Drug Discovery Targeting Viral Metalloenzymes 327 Baohu Li, Hui Xu, Jiahui Zhou, Kai Tang, Xinyong Liu, Jinfei Yang, and Peng Zhan 11 Drug Discovery Targeting Carbonic Anhydrase 371 Weina Zhong, Xueying Li, Wenli Zhang, and Wukun Liu 12 Targeting Autotaxin for Therapeutic Intervention 395 Yangyang Chen, Maolin Duan, Jifa Zhang, and Liang Ouyang 13 Targeting ENPP1 for Therapeutic Intervention 425 Yuyan Han, Yaoliang Sun, and Shilin Xu 14 Drug Discovery Targeting Oxygen-Sensing Hypoxia-Inducible Factor Prolyl Hydroxylases 475 Yue Wu and Xiaojin Zhang 15 Hijacking Histone Demethylase KDM5B for Novel Therapeutics 507 Wen-Long Wang, Guan-Jun Yang, and Bin Yu 16 Advances and Future Directions in Small-Molecule LpxC Inhibitors Targeting Gram-Negative Bacteria 535 Yue Liu and You-Cai Xiao 17 Substrate and Inhibitor Discovery of Human Glutaminyl Cyclases 563 Jun Mou, Xiang-Min Dong, Jing-Wei Wu, Ling-Ling Yang, and Guo-Bo Li 18 Drug Discovery Targeting Tryptophan/Indoleamine 2,3-Dioxygenase 591 Xiang-Li Ning, Lin Ma, and Guo-Bo Li Index 643.