Modelling of Human Leucyl Aminopeptidases for in silico Off Target Binding Analysis of Potential Plasmodium falciparum Leucine Aminopeptidase (PfA-M17) Specific Inhibitors

Title:Modelling of Human Leucyl Aminopeptidases for in silico Off Target Binding Analysis of Potential Plasmodium falciparum Leucine Aminopeptidase (PfA-M17) Specific Inhibitors

Volume: 8 Issue: 3

Author(s): Shakti Sahi, Utkarsh Raj, Meenakshi Chaudhary and Vikrant Nain

Affiliation:

Keywords: Adverse drug event, drug designing, drug toxicity, homology modeling, infectious disease, in silico screening, malaria, molecular docking.

Abstract: Malaria is one of the most widespread infectious diseases in the world. Emergence of multi-drug resistant Plasmodium strains makes it crucial to identify new classes of compounds for anti-malarial therapy. Novel anti-malarial compounds from natural sources (Gomphostema niveum) as well as synthetic chemicals (5-aminolevulinic acid) have been reported in recent patents. Plasmodium falciparum leucyl aminopeptidase (PfA-M17) is a validated target for antimalarial drug development. However, known aminopeptidase inhibitors beset with the problem of non-specificity. Therefore, 3D structural models of PfA-M17 human homologs, Leucine aminopeptidase3 (hLAP3) and probable leucine aminopeptidase (hNPEPL1) were predicted for molecular docking based screening of potential inhibitors for their off target activity. Comparison of IC₅₀ and docking scores of highly active hLAP3 inhibitors shows good correlation (r²≈0.8). Further, docking analysis with potential PfA-M17 inhibitor Compound-X (identified through virtual screening) shows much higher binding affinity towards PfA-M17 (docking score -11.44) than hLAP3 (docking score -4.26) and hNPEPL1 (docking score -5.08). This lead compound, Compound-X can act as a scaffold for further increasing PfA-M17 binding affinity and hLAP3 and hNPEPL1 3D structure models will be useful for screening of PfA-M17 specific inhibitors.

Cite this article as:

Sahi Shakti, Raj Utkarsh, Chaudhary Meenakshi and Nain Vikrant, Modelling of Human Leucyl Aminopeptidases for in silico Off Target Binding Analysis of Potential Plasmodium falciparum Leucine Aminopeptidase (PfA-M17) Specific Inhibitors, Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2014; 8 (3) . https://dx.doi.org/10.2174/1872214808666141001125057