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Aspartate carbamoyltransferase of Plasmodium falciparum as a potential drug target for designing anti-malarial chemotherapeutic agents

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Abstract

Malaria remains one of the leading causes of deaths attributable to a communicable disease globally. The reemergence of drug-resistant Plasmodium falciparum, the most fatal human malarial parasite, has necessitated the exploration of different pathways to provide the urgently required novel drug targets. Aspartate carbamoyltransferase, an enzyme of de novo pyrimidine biosynthetic pathway in Plasmodium represents an attractive drug target. The enzyme was characterized using in silico tools. Tertiary (3D) structure of the enzyme was generated using the structure of Aspartate carbamoyltransferase of Pyrococcus abyssi (PDB ID: 1ML4) as template by comparative modeling and validated by various structural quality validation tools. The model was stable during the simulation with the equilibrium root-mean-square standard deviation value of ~1 Å. Results from structure assessment tools indicated the reasonably good quality of model. Several inhibitor molecules were docked in the active site of the modeled protein for determining the binding affinity of these molecules toward the protein. Out of various inhibitors used in the study, 3-(4-Hydroxy-phenyl)-2-(2-phosphono-acetylamino)-propionic acid showed highest binding affinity towards ACT. This study provides new insights towards understanding the 3-D Pf ACT structure and binding affinity of selected inhibitor compounds and also paves a way for designing novel anti-malarials.

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Acknowledgments

The authors are grateful to Dr. J.S. Yadav, Director, Indian Institute of Chemical Technology, Hyderabad for his continuous support and encouragement. Amit Kumar Banerjee is thankful to Council of Scientific and Industrial Research (CSIR), New Delhi, for Senior Research Fellowship.

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There is no conflict of interest for this study.

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  1. Bioinformatics Group, Biology Division, Indian Institute of Chemical Technology, Tarnaka, Uppal Road, Hyderabad, Andhra Pradesh, 500007, India

    Amit Kumar Banerjee, Neelima Arora & Upadhyayula Surya Narayana Murty

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  1. Amit Kumar Banerjee
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  2. Neelima Arora
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  3. Upadhyayula Surya Narayana Murty
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Correspondence to Upadhyayula Surya Narayana Murty.

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Banerjee, A.K., Arora, N. & Murty, U.S.N. Aspartate carbamoyltransferase of Plasmodium falciparum as a potential drug target for designing anti-malarial chemotherapeutic agents. Med Chem Res 21, 2480–2493 (2012). https://doi.org/10.1007/s00044-011-9757-3

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