| CPC G16B 5/00 (2019.02) [C07K 16/244 (2013.01); G16B 15/30 (2019.02); G16C 20/50 (2019.02); G16C 20/90 (2019.02); C07K 2317/55 (2013.01); C07K 2317/76 (2013.01); G16B 15/00 (2019.02)] | 19 Claims |
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1. A method for manufacturing a ligand having affinity for a binding site of a macromolecular target, the method comprising designing the ligand by:
a) identifying, by one or more processors of a computing system, a target list of atoms forming a surface of the binding site, wherein the atoms in the target list are referred to as target theta atoms;
b) classifying, by the one or more processors, the target theta atoms according to atom type, wherein the atom types of the target theta atoms are referred to as target theta atom types and are selected from a predetermined list of possible theta atom types;
c) extracting, by the one or more processors and from a structural database of biological macromolecules, information about non-bonding, intra-molecular or inter-molecular atom to atom contacts, wherein an atom type of a reference theta atom in a contacting pair of atoms is one of the predetermined list of possible theta atom types, and wherein the atom type of an opposing, reference iota atom of the pair, is one of a predetermined list of possible iota atom types, wherein the information comprises spatial data about the reference iota atom relative to the reference theta atom;
d) collecting, by the one or more processors and from the structural database, data comprising a theta contact set for a plurality of contacts involving further reference theta atoms of the atom type;
e) for each target theta atom identified in the target list, the one or more processors: superimposing, in or around the binding site, data relating to a given iota atom type, or a predetermined group of related iota atom types, from a corresponding theta contact set, the superimposition comprising using the spatial data in the theta contact set for contacts comprising the given iota atom type or one or more of the predetermined group of related iota atom types to determine theoretical locations representing where each iota atom type, or each of the one or more of the predetermined group of related iota atom types, would be located if the theta atom of the contact were located at the position of the corresponding theta atom in the target binding site;
f) combining or parsing, by the one or more processors, the data to predict one or more favored regions of the binding site where the given iota atom type, or the predetermined group of related iota atom types, has high theoretical propensity to be located, the high theoretical propensity being defined as where a density of the determined theoretical locations is above a threshold; and
g) identifying a modification to a candidate ligand, in terms of alternate or additional atoms within the candidate ligand, that produces a greater intersection between the alternate or additional atoms and the favored regions for the respective iota atom types, leading to an improvement in affinity of the candidate ligand as modified to the binding site compared to the candidate ligand without modification, by notionally docking the un- modified candidate ligand into the binding site and comparing, by the one or more processors, the type and position of one or more of the atoms of the candidate ligand with the favored regions for the respective iota atom types;
wherein each non-bonding intra-molecular or inter-molecular contact in the structural database is defined as a contact between opposing residues of a protein fold or between opposing monomer units of a macromolecular fold or between two interacting macromolecular partners and is between a particular reference theta atom on one side of the fold or first interacting partner and a particular reference iota atom on an opposing side or second interacting partner, in an instance where the following condition is satisfied:
s-Rw<t, wherein s represents separation between two atoms of the contact, Rw represents a sum of van der Waals radii of the two atoms of the contact, and t represents a predetermined threshold distance; and
wherein the classification by target theta atom type is unique such that there is no intersection between the data of any theta contact set for a given theta atom type and the data of any other theta contact set for any other theta atom type, apart from data representing contacts involving the given theta atom as the iota atom;
wherein the predetermined group of related iota atom types is one of a plurality of non-overlapping groups obtained by sorting the 167 non-hydrogen atoms present in the 20 natural amino acids of proteins into groups of similar chemical type; and
manufacturing the candidate ligand as modified, wherein the candidate ligand as modified is an antibody.
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