Cathafiline from Cassytha filiformis and BR-Xanthone A from Garcinia mangostana as potential bone morphogenetic protein receptor type I (BMPR-I) inhibitor for iron-refractory iron deficiency anemia in silico

Abstract

Oral iron supplementation has become a standard therapy for anemia around the world but some anemic patients are not responsive to it, as well known as Iron Refractory Iron Deficiency Anemia (IRIDA). One of the causes of IRIDA is BMPR-I activation. LDN-193189 is a synthetic small molecule that is developed for inhibition of BMPR-I. In the human liver, this receptor consists of 4 isoforms of Activin Like Kinase (ALK) 1, 2, 3, and 6. However, the synthetic molecule is not specifically bind to BMPR-I. This study aimed to identify Indonesian phytochemicals that can inhibit BMPR-I as IRIDA therapy with molecular docking approach. This bioinformatics study used 517 phytochemicals, which were registered in HerbalDB, had molecular structure and met the criteria for Lipinski’s rule of five. Three dimensional structure of LDN-193189 as a standard compound was found in complex with BMPR-I subtype ALK2 and obtained from Protein Data Bank (ID: 3Q4U). The AutoDock Vina 1.1.2. software was used to perform molecular docking between LDN-193189-ALK2 and phytochemicals-ALK-2. Binding complexes of ALK2 and LDN-193189/phytochemicals were visualized using PyMol 1.3 and Chimera 1.12 programs. The potential candidate of BMPR-I inhibitor was analysed based on docking score, binding site and conformation of phytochemicals toward ALK2. It revealed that BR-Xanthone A had lower docking score than LDN-193189 (-11.40 kcal/mol vs 11.30 kcal/mol). Phytochemicals which have hydrogen bonds to ATP binding site of ALK2 and similar conformation with LDN-193189 were Cathafiline and BR-Xanthone A. Both of those phytochemicals met the criteria of Lipinski’s rule of five. Cathafiline and BR-Xanthone A were potential as inhibitor BMPR-I for treatment of IRIDA.