Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide-based inhibitor design

Abstract

8Falcipains are major cysteine proteases of Plasmodium falciparum essential in hemoglobin proteases, identification of sequence and structure differences with homologous human 2 2 cathepsins is necessary. The protein substrate processing activity of these proteases is tightly inaccessible. Here, we utilised in silico approaches to determine sequence and structure spot residues, key for maintaining structural integrity of the prodomains as well as conferring 2 7 their inhibitory activity, were identified via residue interaction analysis. Information gathered 2 8 was used to design short peptides able to mimic the prodomain activity on plasmodial

Structure of the Plasmodium falciparum PfSERA5 pseudo‐zymogen

“…PfSERA5PE shares greatest similarity to that of the longer prodomains of the cathepsin-L-like subfamily (L, V, K, S, W, F, and H), which are approximately 100 residues in length and consist of two α-helices followed by a short beta sheet and a third short helix. 39,40 Members of this subfamily contain two distinct conserved sequence motifs within the prodomain, that being ERFNIN and GNFD. 41 Present within falcipains, but not in PfSERA5, these motifs have been identified to contribute to the structure and stability of the prodomain, 42,43 and may contribute to their inhibitory function.…”

“…Although sharing a similar central domain, there is significantly less structural homology between corresponding prodomains within the family (Figure 2c,d), leading to the classification of two subfamilies. PfSERA5PE shares greatest similarity to that of the longer prodomains of the cathepsin‐L‐like subfamily (L, V, K, S, W, F, and H), which are approximately 100 residues in length and consist of two α‐helices followed by a short beta sheet and a third short helix 39,40 . Members of this subfamily contain two distinct conserved sequence motifs within the prodomain, that being ERFNIN and GNFD 41 .…”

Molecular Docking Studies of Rifampicin – rpoB complex: Repurposing Drug Design Implications for against Plasmodium falciparum Malaria through a Computational Approach

“…The recent identification of a relict, non-photosynthetic chloroplast plastid (apicoplast) reported in malarial parasites is aimed as one of a promising potential new target for drug therapy in malaria 7 8 9 . The apicoplast contains a range of metabolic pathways and processes that differ radically to those of the host thereby offering opportunities and presenting ideal strategies for antimalarial drug therapy.…”

iAMAP-SCM: A Novel Computational Tool for Large-Scale Identification of Antimalarial Peptides Using Estimated Propensity Scores of Dipeptides

“…Both molecular docking and MD simulations were able to elucidate the interactions between novel phenylalanine–glycine dipeptide sulfonamide conjugate compounds and target protein residues. − To validate the antiplasmodial activity of cyclic peptides engineered from phytocystatin against falcipain (cysteine proteases from the malarial parasite P. falciparum), protein–peptide docking and MD simulations were performed to calculate the free energy of ligand–enzyme binding. , Moreover, MD experiments of the interaction between a potential drug target PFI1625c (a metalloprotease present in P. falciparum) and several bioactive peptides have been performed to screen for AMAPs with high affinity .…”

“…22−24 To validate the antiplasmodial activity of cyclic peptides engineered from phytocystatin against falcipain (cysteine proteases from the malarial parasite P. falciparum), protein−peptide docking and MD simulations were performed to calculate the free energy of ligand−enzyme binding. 25,26 Moreover, MD experiments of the interaction between a potential drug target PFI1625c (a metalloprotease present in P. falciparum) and several bioactive peptides have been performed to screen for AMAPs with high affinity. 27 Although these two computational techniques could enable the discovery of new AMAPs, all these approaches might be limited in the large-scale identification of new AMAPs from a vast number of candidate peptides.…”