Li Hanxuan, Ibrahim Mohamed Moustafa, Chen Hao, Li Wei, Jablonski Monica M
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Pharmaceuticals (Basel). 2021 Aug 31;14(9):887. doi: 10.3390/ph14090887.
Glaucoma is a leading cause of permanent vision loss and current drugs do not halt disease progression. Thus, new therapies targeting different drug targets with novel mechanisms of action are urgently needed. Previously, we identified CACNA2D1 as a novel modulator of intraocular pressure (IOP) and demonstrated that a topically applied CACNA2D1 antagonist-pregabalin (PRG)-lowered IOP in a dose-dependent manner. To further validate this novel IOP modulator as a drug target for IOP-lowering pharmaceutics, a homology model of CACNA2D1 was built and docked against the NCI library, which is one of the world's largest and most diverse compound libraries of natural products. Acivicin and zoledronic acid were identified using this method and together with PRG were tested for their plausible IOP-lowering effect on Dutch belted rabbits. Although they have inferior potency to PRG, both of the other compounds lower IOP, which in turn validates CACNA2D1 as a valuable drug target in treating glaucoma.
青光眼是导致永久性视力丧失的主要原因，目前的药物无法阻止疾病进展。因此，迫切需要针对具有新作用机制的不同药物靶点的新疗法。此前，我们将CACNA2D1鉴定为眼内压（IOP）的新型调节剂，并证明局部应用的CACNA2D1拮抗剂——普瑞巴林（PRG）——以剂量依赖方式降低眼内压。为了进一步验证这种新型眼内压调节剂作为降低眼内压药物的药物靶点，构建了CACNA2D1的同源模型，并将其与NCI库对接，NCI库是世界上最大、最多样化的天然产物化合物库之一。使用该方法鉴定出阿西维辛和唑来膦酸，并与PRG一起测试它们对荷兰带兔可能的降低眼内压作用。尽管它们的效力低于PRG，但其他两种化合物均能降低眼内压，这反过来验证了CACNA2D1作为治疗青光眼的有价值药物靶点。
