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Deorphanization of Malonyl CoA:ACP Transacylase Drug Target in Plasmodium falciparum (PfFabD) Using Bacterial Antagonists: A Piggyback' Approach for Antimalarial Drug Discovery

Sreshty, Asha Latha M and Surolia, Avadhesha and Sastry, Narahari G and Murty, Suryanarayana U (2012) Deorphanization of Malonyl CoA:ACP Transacylase Drug Target in Plasmodium falciparum (PfFabD) Using Bacterial Antagonists: A Piggyback' Approach for Antimalarial Drug Discovery. In: Molecular informatics, 31 (3-4). pp. 281-299.

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Official URL: http://onlinelibrary.wiley.com/doi/10.1002/minf.20...

Abstract

Quest for new drug targets in Plasmodium sp. has underscored malonyl CoA:ACP transacylase (PfFabD) of fatty acid biosynthetic pathway in apicoplast. In this study, a piggyback approach was employed for the receptor deorphanization using inhibitors of bacterial FabD enzymes. Due to the lack of crystal structure, theoretical model was constructed using the structural details of homologous enzymes. Sequence and structure analysis has localized the presence of two conserved pentapeptide motifs: GQGXG and GXSXG and five key invariant residues viz., Gln109, Ser193, Arg218, His305 and Gln354 characteristic of FabD enzyme. Active site mapping of PfFabD using substrate molecules has disclosed the spatial arrangement of key residues in the cavity. As structurally similar molecules exhibit similar biological activities, signature pharmacophore fingerprints of FabD antagonists were generated using 0D-3D descriptors for molecular similarity-based cluster analysis and to correlate with their binding profiles. It was observed that antagonists showing good geometrical fitness score were grouped in cluster-1, whereas those exhibiting high binding affinities in cluster-2. This study proves important to shed light on the active site environment to reveal the hotspot for binding with higher affinity and to narrow down the virtual screening process by searching for close neighbors of the active compounds.

Item Type: Journal Article
Keywords: Plasmodium falciparum;Malonyl CoA:ACP Transacylase;Active site mapping;Pharmacophore fingerprinting;Cluster analysis; Virtual screening
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 14 Aug 2012 05:15
Last Modified: 14 Aug 2012 05:16
URI: http://eprints.iisc.ernet.in/id/eprint/44491

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