Structure of plasmepsin v in complex with an inhibitor and uses thereof
AssigneeThe Walter and Eliza Hall Institute of Medical Research
InventorsJustin BODDEY, Alan COWMAN, Peter CZABOTAR, Tony HODDER, Brad SLEEBS
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Abstract
In one aspect, the present invention relates to the crystal structure of Plasmodium vivax plasmepsin V in complex with an inhibitor, and to methods of using the crystal structure and related structural information to identify, design and/or screen for inhibitors or redesign known inhibitors that interact with and/or modulate plasmepsin V activity. In another aspect, the present invention relates to a class of compounds based on the inhibitor useful in the treatment of malaria.
Claims29
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A method of identifying, designing and/or screening for a compound that can potentially interact with plasmepsin V and/or mimic WEHI-842 interacting with plasmepsin V, including performing structure-based identification, design and/or screening of a compound based on (i) the compound's interaction with a plasmepsin V structure and/or (ii) the compound's similarity with a WEHI-842 structure in complex with a plasmepsin V structure defined by the atomic coordinates of Appendix I or a subset thereof.
A method of identifying an inhibitor compound comprising an entity selected from the group consisting of an antibody, an antigen-binding fragment, a peptide, a non-peptide molecule and a chemical compound, wherein said inhibitor compound is capable of blocking biological activity resulting from an interaction with plasmepsin V, wherein said method includes:
- introducing into a suitable computer program parameters defining an interacting surface based on the conformation of plasmepsin V in complex with WEHI-842 corresponding to the atomic coordinates of Appendix I or a subset thereof, wherein said program displays a three-dimensional model of the interacting surface;
- creating a three-dimensional structure of a test compound in said computer program;
- displaying a superimposing model of said test compound on the three-dimensional model of the interacting surface;
- assessing whether said superimposing model of said test compound fits spatially and optionally energetically into a binding site;
- synthesising said test compound;
- incorporating said test compound in a biological activity assay;
- and
- determining whether said test compound inhibits the biological activity of plasmepsin V
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Use of the atomic coordinates or a subset thereof as shown in Appendix I at least representing:
- (i) the enzyme domain of plasmepsin V;
- (ii) the N-terminal subdomain of plasmepsin V;
- (iii) the C-terminal subdomain of plasmepsin V;
- (iv) the substrate-binding site of plasmepsin V;
- (v) the flap from the N-terminal subdomain from plasmepsin V;
- (vi) one or more regions of the flap in complex with WEHI-842;
- and/or
- (vii) one or more regions of the substrate-binding site in complex with WEHI-842,
- in identifying, designing and/or screening for a compound that can potentially interact with plasmepsin V or mimic WEHI-842 interacting with plasmepsin V, including performing structure-based identification, design and/or screening of a compound based on the compound's interactions with a plasmepsin V structure as defined by the atomic coordinates or a subset thereof or the compound's similarity with WEHI-842 in complex with plasmepsin V as defined by the atomic coordinates or a subset thereof.
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A method of re-designing a compound which is known to bind to plasmepsin V comprising performing structure-based evaluation of the compound based on the compound's interactions with a plasmepsin V structure defined by the atomic coordinates of Appendix I or a subset thereof and/or the compound's similarity with a structure of WEHI-842 in complex with plasmepsin V as defined by the atomic coordinates of Appendix I or a subset thereof;
- and re-designing or chemically modifying the compound as a result of the evaluation.
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A computer-assisted method of identifying a molecule able to interact with plasmepsin V using a programmed computer comprising a processor, which method comprises the steps of:
- (a) generating, using computer methods, a set of atomic coordinates of a structure that possesses energetically favourable interactions with the atomic coordinates of:
- (i) the substrate-binding site of plasmepsin V, the structure being defined by a subset of the atomic coordinates shown in Appendix I;
- and/or
- (ii) at least portions of plasmepsin V, preferably including the flap, the structure being defined by a subset of the atomic coordinates shown in Appendix I, which coordinates are entered into the computer thereby generating a criteria data set;
- (b) comparing, using the processor, the criteria data set to a computer database of chemical structures;
- (c) selecting from the database, using computer methods, chemical structures which are complementary or similar to a region of the criteria data set;
- and
- (d) optionally, outputting, to an output device, the selected chemical structures which are complementary to or similar to a region of the criteria data set.
A computer-assisted method of identifying potential mimetics of WEHI-842 using a programmed computer comprising a processor, the method comprising the steps of:
- (a) generating a criteria data set from a set of atomic coordinates of:
- (i) the substrate-binding site of plasmepsin V, the structure being defined by a subset of the atomic coordinates shown in Appendix I;
- (ii) at least a portion of plasmepsin V, preferably including the flap, the structure being defined by a subset of the atomic coordinates shown in Appendix I;
- and/or WEHI-842, the structure being defined by a subset of the atomic coordinates shown in Appendix I, which coordinates are entered into the computer;
- (b):
- (i) comparing, using the processor, the criteria data set to a computer database of chemical structures stored in a computer data storage system and selecting from the database, using computer methods, chemical structures having a region that is structurally similar to the criteria data set;
- or
- (ii) constructing, using computer methods, a model of a chemical structure having a region that is structurally similar to the criteria data set;
- and
- (c) optionally, outputting to an output device:
- (i) the selected chemical structures from step (b)(i) having a region similar to the criteria data set;
- or
- (ii) the constructed model from step (b)(ii).
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Dependencies are inferred from the claim text.