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The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Christina Spry, Anthony G. Coyne
Crystals of L. major coproporphyrinogen III oxidase, an enzyme involved in porphyrin biosynthesis, were soaked with 66 different fragment cocktails. Co-crystal structures were obtained for two fragments each from different cocktails (Table 2). Interestingly, one of the two fragment hits, cyclopentyl acetate, was observed to bind at three positions within the active site. In the same structure, one molecule of acetate (co-purified with the enzyme) was also bound. The four carboxylates contributed by the three fragment molecules and the acetate molecule were predicted to occupy the binding sites of the four carboxylates of the natural substrate coproporphyinogen-III.
Neurological and neuropsychiatric manifestations of porphyria
Published in International Journal of Neuroscience, 2019
Yiji Suh, Jason Gandhi, Omar Seyam, Wendy Jiang, Gunjan Joshi, Noel L. Smith, Sardar Ali Khan
HC results when coproporphyrinogen III oxidase does not function properly. Coproporphyrinogen III oxidase is a mitochondrial enzyme that is responsible for catalyzing the sixth step of heme biosynthesis. This defect in enzyme is inherited as an autosomal dominant disorder [9]. When patients with HC are tested, it is revealed threat their δ-aminolaevulinic acid synthase is increased and coproporhyringogen oxidase is depressed. This supports the inference that an enzyme is malfunctional within the heme biosynthetic pathway, causing this disease to manifest [10]. This defect can cause gastrointestinal and neuropsychiatric symptoms as well as skin lesions. Skin photosensitivity are also sometimes present. A study by Brodie et al. determined that around 23% of people had neurologic manifestations, 23% had psychiatric disorders, 29% were sensitive to light, and 80% had pain within the abdominal regions [11].