Designing dual inhibitors against potential drug targets of Plasmodium falciparum -M17 Leucyl Aminopeptidase and Plasmepsins

Abstract

Malaria is one of the major diseases of concern worldwide, especially in the African regions. According to a recent WHO report, 95% of deaths that occur due to malaria are in the African regions. Resistance to present antimalarial drugs is increasing rapidly and becoming a problem of concern. M17 Leucyl Aminopeptidase (PfM17LAP) and vacuolar Plasmepsins (PfPM) are two important enzymes involved in the haemoglobin degradation pathway of Plasmodium falciparum. PfM17LAP regulates the release of amino acids and PfPM mediates the conversion of haemoglobin proteins to oligopeptides. These enzymes thus play an essential role in the survival of malaria parasites inside the human body. In the present study, we used in-silico molecular docking, simulation and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) studies to find potential dual inhibitors of PfPM and PfM17LAP using the ChEMBL antimalarial library. Absorption, distribution, metabolism, excretion and toxicity (ADMET) profiling of the top ten ranked molecules was done using the BIOVIA Discovery Studio. The present investigation revealed that the compound CHEMBL426945 is stable in the binding site of both PfPM and PfM17LAP. In this study, we have reported novel dual-inhibitors that may act better than the present antimalarial drugs.

Communicated by Ramaswamy H. Sarma

Keywords:

• Malaria
• M17 Leucyl Aminopeptidase
• plasmepsins
• ADMET
• MMPBSA

Disclosure statement

No potential conflict of interest was reported by the authors.

Authors’ contributions

The work was designed and conceptualised by GRD, MK and NS. The experiments were carried out by GRD and AJ. Data analysis was done by GRD, AJ, MK and NS. Resources were provided by MK and NS. The manuscript was prepared and written by GRD and AJ. All authors reviewed and edited the manuscript.

Additional information

Funding

We acknowledge the Indian Council for Medical Research (ICMR) for funding the BIOVIA Discovery Studio [Grant number: ISRM/12(43)/2019/ ID No. 2019-2501] and University of Delhi [Faculty Research Programme Grant under Institute of Eminence Ref. No./IoE/2021/12/FRP]. GRD and AJ are supported by the University Grants Commission (UGC) Fellowship under grant numbers [Sch/139/Non-NETBiophy./Ph.D.//2019-20/860] and [UGC-Ref. No.: 5513/(CSIR-UGC NET JUNE 2019)] respectively.