In Silico Analysis and Docking Studies on Cystic Fibrosis to identify Potential Drug Candidates

Abstract

Cystic fibrosis (CF) is a multi-system autosomal recessive disorder due to defects in the CF transmembrane conductance regulator (CFTR) protein, most commonly affecting the lungs. Despite being thought of as an uncommon ailment, cystic fibrosis (CF) is the most common monogenic sickness among those who are mostly of European descent. It is estimated that 1% of people worldwide have a single faulty copy of the CFTR gene. A recent pilot study using NGS technology in 2020 from Delhi’s Sir Ganga Ram Hospital, indicated the prevalence of cystic fibrosis mutations of 1 in 2,000 persons. This is much higher than the earlier estimated prevalence as the disease was rare in the Indian population. The most common mutations are delta F 508 and G551D which are also prevalent in the Indian population. The use of computer-aided drug design (CADD) can reduce the time needed for the discovery, evaluation and structure-optimization of new therapeutic candidates. CADD may be advantageous for pharmaceuticals with logical designs. Multiple breakthroughs have been made in the study of small molecule medicines and natural chemicals for the treatment of cystic fibrosis. Seven well-known small-molecule medications that target the CFTR were chosen including Ivacaftor, Lumacaftor, Tezacaftor, Galicaftor, Olacaftor, Navocaftor and Elexacaftor. The natural compounds chosen were Genistein, Curcumin and Resveratrol. They were all docked onto the CFTR target protein and the effectiveness of the therapy was evaluated based on the docking scores. It was also planned to investigate if the combined impacts of these two different kinds of molecules may help in the development of new medications. To achieve this, combinatorial docking was tried using the small molecule market medication and the natural chemical that showed the best interaction with the target protein. Finally, based on molecular docking studies, Lonidamine, a well-known medicinal molecule was used to determine whether it may target cystic fibrosis.