Figure 5.

New functions conferred by new chemotypes discovered by docking. (A) The β-lactam inhibitor clavulanic acid up-regulates the expression of β-lactamase in E. cloacae, antagonizing the efficacy of the primary β-lactam antibiotics ceftazidime (CAZ) and piperacillin (PIP) in a disk diffusion assay (left).^47,197 In contrast, the docking-discovered inhibitors simply inhibit the enzyme without up-regulating it, synergizing with the same primary antibiotics (right). (B) Lorazepam (left) and ogerin (middle) are both modeled to bind at the same site on GPR68. Ogerin, however, is more potent and specific than lorazepam. In wild-type mice, ogerin reduces fear conditioning in a contextual freezing assay compared to knockout mice, where it has no measurable effect (right). Reproduced with permission from Nature (Huang, X. P.; et al. Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65; 2015, 527, 477–483);²⁵⁶ Copyright 2015 Macmillan Publishers Ltd. (C) Inhibition of visceral hypersensitivity in IBS rat model. Therapeutic effects of compound 15 in IBS rats. The pain threshold decreased in response to CRD (at score 3 (left) and score 4 (right)).²⁰¹ (D) Left panel. Xenograft tumor growth of human lung cancer cell line H2122, 50 mg kg⁻¹ day⁻¹ RBC8 initiated 24 h after inoculation inhibited tumor growth. Typical tumor appearance at 21 days is shown. Right panel. Effect of RBC8 on H358 xenograft models. RBC8 treatment (50 mg kg⁻¹ day⁻¹) initiated 24 h after inoculation inhibited xenograft tumor growth of human lung cancer cell line H358. Data represent the mean ± SEM of six mice. Tumor volume in the treatment group was statistically different from controls as determined by the Student’s t test. Reproduced with permission from Nature (Yan, C.; et al. Discovery and characterization of small molecules that target the GTPase Ral; 2014, 515, 443–447);²⁰² Copyright 2014 Macmillan Publishers Ltd.