A Molecular Modeling Approach to Identify Potential Antileishmanial Compounds Against the Cell Division Cycle (cdc)-2-Related Kinase 12 (CRK12) Receptor of Leishmania donovani
Date
2021
Journal Title
Journal ISSN
Volume Title
Publisher
biomolecules
Abstract
The huge burden of leishmaniasis caused by the trypanosomatid protozoan parasite Leishmania
is well known. This illness was included in the list of neglected tropical diseases targeted for elimination
by theWorld Health Organization. However, the increasing evidence of resistance to existing antimonial
drugs has made the eradication of the disease difficult to achieve, thus warranting the search for
new drug targets. We report here studies that used computational methods to identify inhibitors
of receptors from natural products. The cell division cycle-2-related kinase 12 (CRK12) receptor is a
plausible drug target against Leishmania donovani. This study modelled the 3D molecular structure of
the L. donovani CRK12 (LdCRK12) and screened for small molecules with potential inhibitory activity
from African flora. An integrated library of 7722 African natural product-derived compounds and
known inhibitors were screened against the LdCRK12 using AutoDock Vina after performing energy
minimization with GROMACS 2018. Four natural products, namely sesamin (NANPDB1649), methyl
ellagic acid (NANPDB1406), stylopine (NANPDB2581), and sennecicannabine (NANPDB6446) were
found to be potential LdCRK12 inhibitory molecules. The molecular docking studies revealed two
compounds NANPDB1406 and NANPDB2581 with binding affinities of 9.5 and 9.2 kcal/mol,
respectively, against LdCRK12 which were higher than those of the known inhibitors and drugs,
including GSK3186899, amphotericin B, miltefosine, and paromomycin. All the four compounds
were predicted to have inhibitory constant (Ki) values ranging from 0.108 to 0.587 M. NANPDB2581,
NANPDB1649 and NANPDB1406 were also predicted as antileishmanial with Pa and Pi values of 0.415
and 0.043, 0.391 and 0.052, and 0.351 and 0.071, respectively. Molecular dynamics simulations coupled
with molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) computations reinforced their
good binding mechanisms. Most compounds were observed to bind in the ATP binding pocket of the
kinase domain. Lys488 was predicted as a key residue critical for ligand binding in the ATP binding
pocket of the LdCRK12. Themoleculeswere pharmacologically profiled as druglikewith inconsequential
toxicity. The identified molecules have scaffolds that could form the backbone for fragment-based drug
design of novel leishmanicides but warrant further studies to evaluate their therapeutic potential.
Description
Research Article
Keywords
Leishmaniasis, Leishmania donovani;, CRK12, molecular docking;, molecular dynamics, natural products;, leishmanicide
Citation
https://doi.org/10.3390/ biom11030458