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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography	Double drugging of prolyl-tRNA synthetase provides a new paradigm for anti-infective drug development Yogavel Manickam , Nipun Malhotra , Siddhartha Mishra , Palak Babbar , Abhishek Dusane , Benoît Laleu , Valeria Bellini , Mohamed-Ali Hakimi , Alexandre Bougdour , Amit Sharma Plos Pathogens 18 DOI: 10.1371/journal.ppat.1010363 Diamond Proposal Number(s): [19946] Open Access Show Abstract ▼ Abstract: Toxoplasmosis is caused by Toxoplasma gondii and in immunocompromised patients, it may lead to seizures, encephalitis or death. The conserved enzyme prolyl-tRNA synthetase (PRS) is a validated druggable target in Toxoplasma gondii but the traditional ‘single target–single drug’ approach has its caveats. Here we describe two potent inhibitors namely halofuginone (HFG) and a novel ATP mimetic (L95) that bind to Toxoplasma gondii PRS simultaneously at different neighbouring sites to cover all three of the enzyme substrate subsites. HFG and L95 act as one triple-site inhibitor in tandem and form an unusual ternary complex wherein HFG occupies the 3’-end of tRNA and the L-proline (L-pro) binding sites while L95 occupies the ATP pocket. These inhibitors exhibit nanomolar IC50 and EC50 values independently, and when given together reveal an additive mode of action in parasite inhibition assays. This work validates a novel approach and lays a structural framework for further drug development based on simultaneous targeting of multiple pockets to inhibit druggable proteins	Mar 2022
I03-Macromolecular Crystallography	Inhibition of Plasmodium falciparum Lysyl‐tRNA synthetase via a piperidine‐ring scaffold inspired Cladosporin analogues Palak Babbar , Mizuki Sato , Yogavel Manickam , Siddhartha Mishra , Karl Harlos , Swati Gupta , Suhel Parvez , Haruhisa Kikuchi , Amit Sharma Chembiochem DOI: 10.1002/cbic.202100212 Diamond Proposal Number(s): [19946] Show Abstract ▼ Abstract: Plasmodium falciparum lysyl tRNA synthetase ( Pf KRS) represent a promising therapeutic anti‐malarial target. Cladosporin, a tool compound was identified as a selective and potent PfKRS inhibitor but lacks metabolic stability. Here, we report chemical synthesis, biological evaluation and structural characterization of analogues where the tetrahydropyran (THP) frame of cladosporin is replaced with the piperidine ring bearing functional group variations. Thermal binding, enzymatic, kinetic and parasitic assays complemented with x‐ray crystallography reveals compounds to be of moderate potency. Co‐crystals of Cla‐B and Cla‐C with PfKRS reveals key atomic configurations that allow drug binding to, and inhibition of the enzyme. Collectively, these piperidine ring scaffold inhibitors lays a framework for further structural editing and functional modifications of cladosporin scaffold to obtain a potent lead.	May 2021

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