E-pharmacophore based virtual screening of potent lead molecules against Cystic Fibrosis: An in silico study

Abstract

Cystic fibrosis is an autosomal recessive condition caused by mutations in the CFTR gene, which encodes the CFTR protein. Currently, CF is a life-limiting illness that has a limited cure. The present study aimed to identify top leads against CFTR protein with F508del in comparison with Lumacaftor. In this study, a homology model of the NBD domain of CFTR protein was developed using the available NBD domain crystal structure. The protein model was refined through apo dynamics. Energy-optimized pharmacophore mapping was carried out to identify essential features for CFTR, resulting in a model with a hydrogen-bond donor, two hydrogen-bond acceptors, and three aromatic ring sites. A screening of a compound from the NPASS database using these DAARRR six-point-pharmacophore features led to the identification of potential ligands that could act against CFTR protein. Further studies such as ADME/T, molecular dynamics, MM_GBSA, and DFT were performed to identify the top-hit compound from the NPASS database. The compound Anguibactin (NPC41982) has been identified as a top lead that exhibits higher binding affinity and stability than the reference compound Lumacaftor, suggesting their potential to bind to the active site of the CFTR protein. These compounds could serve as starting points for the development of drug-like molecules for treating cystic fibrosis.