Target Specific Drug Repurposing for Cystic Fibrosis: An in-Silico approach
Author(s)
ABSTRACT WITHDRAWN
OBJECTIVES Cystic Fibrosis (CF), a fatal genetic disorder, is common in Northern European descendant populations and occurs in 1 out of 3000 infants. CF is a resultant of mutation in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that regulates chloride-sodium movement through the epithelial cell membranes is expressed in epithelial cells of lungs and pancreas. Deletion of Phenylalanine at 508 position (∆F508del mutation) in the chromosome 7q31.2 results in abnormal CFTR protein. This abnormal protein is responsible for disparity in the transport of ions mainly chloride and sodium, causes building up of dense mucus and bacterial colonization in the respiratory tract which in turn evokes the inflammatory response, this persistent inflammation results in airway damage. CF is categorized under rare diseases and till date only three drugs have been approved for its treatment, this startling situation demands extensive drug research. The objective of this study is to identify potential drugs for CFTR through in silico approach. METHODS Drug repurposing hub was used for the identification of drugs for the target CFTR. DrugBank (DB) database was used to identify drugs that are similar with the above standard drugs for CFTR target and further taken for docking studies and free binding energy (𝛥G) analysis using Schrodinger Glide and Prime tools. RESULTS Five standards were obtained from Drug Repurposing Hub: Ivacaftor, Lumacaftor, Tezacaftor, Ataluren and Glafenine. Subsequently, upon similarity search, 143 similar structures were obtained for the above standard drugs. Amongst them Cenerimod, Floctafenine, Roquinimex, Nadifloxacin and (3Z)-6-(4-HYDROXY-3-METHOXYPHENYL)-3-(1H-PYRROL-2-YLMETHYLENE)-1,3-DIHYDRO-2H-INDOL-2-ONE exhibited better docking scores against CFTR and were found to possess good oral absorption (>70%) and high 𝛥G values. CONCLUSION Our study concluded that Cenerimod, Floctafenine, Roquinimex, Nadifloxacin and (3Z)-6-(4-HYDROXY-3-METHOXYPHENYL)-3-(1H-PYRROL-2-YLMETHYLENE)-1,3-DIHYDRO-2H-INDOL-2-ONE are potential drugs against CFTR and could be repurposed for CF.
Conference/Value in Health Info
2021-05, ISPOR 2021, Montreal, Canada
Value in Health, Volume 24, Issue 5, S1 (May 2021)
Code
PRO42
Topic
Methodological & Statistical Research
Disease
Rare and Orphan Diseases