Oligopeptidase B and B2: comparative modelling and virtual screening as searching tools for new antileishmanial compounds

Abstract

Leishmaniasis are diseases caused by parasites of the genus Leishmania and transmitted to humans by the bite of infected insects of the subfamily Phlebotominae. Current drug therapy shows high toxicity and severe adverse effects. Recently, two oligopeptidases (OPBs) were identified in Leishmania amazonensis, namely oligopeptidase B (OPB) and oligopeptidase B2 (OPB2). These OPBs could be ideal targets, since both enzymes are expressed in all parasite lifecycle and were not identified in human. This work aimed to identify possible dual inhibitors of OPB and OPB2 from L. amazonensis. The three-dimensional structures of both enzymes were built by comparative modelling and used to perform a virtual screening of ZINC database by DOCK Blaster server. It is the first time that OPB models from L. amazonensis are used to virtual screening approach. Four hundred compounds were identified as possible inhibitors to each enzyme. The top scored compounds were submitted to refinement by AutoDock program. The best results suggest that compounds interact with important residues, as Tyr490, Glu612 and Arg655 (OPB numbers). The identified compounds showed better results than antipain and drugs currently used against leishmaniasis when ADMET in silico were performed. These compounds could be explored in order to find dual inhibitors of OPB and OPB2 from L. amazonensis.

Characterization of Leishmania (L.) amazonensis oligopeptidase B and its role in macrophage infection

“…These findings were expected, since OPB sequence conservation was observed among Leishmania species. The lack of OPB in mammals has prompted some groups to search for potential OPB or OPB/OPB2 inhibitors as eventual drugs for leishmaniasis (Goyal et al ., 2014; Sodero et al ., 2017). The conservation in OPB activity among the 3 species analysed ( L. ( L. ) major and L. ( L. ) donovani and L. ( L. ) amazonensis , in this work) suggests that drugs designed for 1 species would probably be effective for others.…”

“…OPB-2 amino acid sequences are conserved among Leishmania but display several insertions and deletions and a C-terminal extension domain when compared to OPBs (de Matos Guedes et al, 2008). No enzymatic or functional studies for OBP-2 were reported to date, but comparative modelling indicates that L. (L.) amazonensis OPB and OPB2 have many similarities and may be sensitive to dual inhibitors (Sodero et al, 2017). OPB is secreted by Leishmania, as it was found in exosomes shed by L. (L.) donovani and L. (L.) major promastigotes (Silverman et al, 2008(Silverman et al, , 2010.…”