Computer aided study on cyclic tetrapeptide based ligands as potential inhibitors of Proplasmepsin IV

Abstract

The belief that we could always stay ahead of the pathogens was forced upon scientists in the whole world by antimicrobial resistance. According to several reports, there are medications that are yet to be made public in the pipeline and there are little motivations to design novel antimicrobials to combat the worldwide drug resistance issues. Presently, the desire to design and develop efficient novel anti-bacterial agents is very high by researchers; thus, this study focuses on identifying the interactions between the studied ligands and Proplasmepsin IV, as well as examining the relationship between the calculated descriptors and binding affinities. This work shows successful prediction of the reacting and inhibiting efficiency of ten (10) cyclic tetra-peptides using insilico method. The optimization of the studied compound revealed the proficiency of methyl (3S,9S,12S)-12-(1,3-dioxoisoindolin-2-yl)-9-(2-(methylthio)ethyl)-5,8,11-trioxo-4,7,10-triaza-1(1,3)-benzenacyclotridecaphane-3-carboxylate (F5) and 2-((3S,9S,12S)-12-(1,3-dioxoisoindolin-2-yl)-3-(methoxycarbonyl)-5,8,11-trioxo-4,7,10-triaza-1(1,3)-benzenacyclotridecaphane-9-yl)acetic acid (F7) to react more than the remaining molecules in term of HOMO and LUMO energies. In comparison, compound F9 demonstrated a higher inhibitory activity than the reference drug, Chloroquine, based on binding affinity. Molecular dynamics simulations over a 100 ns period further explored the binding affinity between F9 and the reference drug. The results showed that the reference drug (- 21.91 ± 1.16 kcal/mol) had a slightly stronger binding affinity than the F9_complex (- 13.85 ± 0.72 kcal/mol). Additionally, pharmacokinetic studies for F9 were compared with those of the reference compound and presented accordingly.