Discovery of novel potent drugs for influenza by inhibiting the vital function of neuraminidase via fragment-based drug design (FBDD) and molecular dynamics simulation strategies

Abstract

The current work describes a fragment linking methodology to generate new neuraminidase inhibitors. A total number of 28,977 fragments from Zinc 20 have been obtained and screened for neuraminidase receptor affinity. Using Schrödinger software, the highest-scoring 270 fragment hits (with scores greater than −7.6) were subjected to fragment combining to create 100 new molecules. These 100 novel compounds were studied using XP docking to evaluate the molecular interaction modes and their binding affinity to neuraminidase receptor. The top ten molecules were selected, for ADMET, drug-likeness features. Based on these characteristics, the best four developed molecules and Zanamivir were submitted to a molecular dynamics simulation investigation to estimate their dynamics within the neuraminidase receptor using Gromacs software. All MD simulation findings show that the generated complexes are very stable when compared to the clinical inhibitor (Zanamivir). In addition, the four designed neuraminidase inhibitors formed very stable complexes with neuraminidase receptor (with total binding energies ranging from −83.50 to −107.85 Kj/mol) according to the total binding energy calculated by MM-PBSA. For the objective of developing new influenza medications, these novel molecules have the potential to be further evaluated in vitro and in vivo for influenza drug discovery. Communicated by Ramaswamy H. Sarma