Claims Analysis
Total Claims: 15
Claim 1
Independent Claim
576 words
A process for drug candidate identification, said
process comprising the steps of: (1) obtaining a computerised representation of the
three-dimensional structure of a binding site on the
surface of a biological macromolecule; (2) generating a computerised model of the functional
structure of said binding site which may be used to
identify favourable and unfavourable interactions
between the binding site and a drug candidate molecule; (3) identifying a molecular fragment capable of
placement within said binding site and capable of
carrying at least one substituent group, said molecular
fragment either being capable of being synthesized from
reagent compounds accessible in substituted form whereby
to import said substituent groups on synthesis of said
molecular fragment or being present in an accessible
reagent compound capable of substitution with said
substituent groups by reaction with further accessible
reagent compounds; (4) generating a set of lists of accessible reagent
compounds, the lists being such that a combination of
compounds taken from each list may be reacted to produce
a candidate compound comprising said molecular fragment
carrying a plurality of substituent groups thereby
generating a first virtual library of candidate
compounds being the theoretical set of compounds
producible by reaction of the members of said lists,
each member of each list comprising a component common
to the other members of that list and a component unique
within that list; (5) for each said list limiting the number of members
thereof using a first set of exclusion rules thereby to
generate a restricted second virtual library of
candidate compounds, the operation of said first set of
rules involving for each member of each list
computerised comparison for favourable or unfavourable
interactions between said computerised model and a
structure comprising said molecular fragment and a
substituent deriving from the unique component within
said list of that member, the molecular fragment and the
computerised model being held in fixed spatial
relationship to each other for said comparison; (6) evaluating and ranking by computer the members of
said second virtual library for favourable and
unfavourable interactions with said computerised model
and thereby generating a restricted third virtual
library of candidate compounds ranked as having
favourable interactions; (7) optionally, selecting from said third virtual
library at least one further molecular fragment and
repeating steps (4), (5) and (6) to generate an
alternative third virtual library; (8) screening said third virtual library using a second
set of exclusion rules thereby to generate a restricted
fourth virtual library of candidate compounds comprising
compounds which are candidates for synthesis and
experimental evaluation for drug efficacy; (9) synthesizing some or all candidate compounds of
said fourth virtual library to produce a candidate
compound library; (10) experimentally evaluating the compounds of said
candidate compound library for drug efficacy; (11) analysing the experimental efficacy data generated
in step (10) for structure-activity relationship
information; (12) using the information derived in step (11)
selecting a revised set of lists of accessible reagent
compounds, said lists being expanded to include selected
reagents not present in the restricted lists generated
in step (5) and optionally restricted to exclude
selected reagents present in the restricted lists
generated in step (5); (13) repeating steps (6) and (7) to identify further
compounds which are candidates for synthesis and
experimental evaluation for drug efficacy; (14) synthesising and experimentally evaluating said
further compounds for drug efficacy; (15) if required repeating steps (11) to (14) one or
more times; (16) identifying as a lead candidate a compound
synthesized and experimentally evaluated as above.
Claim 2
Dependent Claim
45 words
A process according to claim 1 wherein in step (7)
at least one further molecular fragment is selected from
the third virtual library, whereafter steps (4), (5) and
(6) are repeated to generate an alternative third
virtual library which is subsequently screened in step
(8).
Claim 3
Dependent Claim
46 words
A process according to either of claims 1 and 2
wherein in step (12) said revised set of lists of
accessible reagents is selected to include reagents
excluded from the restricted lists generated in step (5)
for being analogs of reagents included in said
restricted lists.
Claim 4
Dependent Claim
48 words
A process according to any one of claims 1 to 3
wherein in step (12) said revised set of lists of
accessible reagents is selected to include reagents
excluded from the restricted lists generated in step (5)
for involving complex transformation in their synthesis
from commercially available reagents.
Claim 5
Dependent Claim
50 words
A process according to any one of claims 1 to 4
wherein in step (12) said revised set of lists of
accessible reagents is selected to include reagents
excluded from the restricted lists generated in step (5)
for being produced in low yield in their synthesis from
commercially available reagents.
Claim 6
Dependent Claim
48 words
A process according to any one of claims 1 to 5
wherein in step (12) said revised set of lists of
accessible reagents is selected to include reagents
excluded from the restricted lists generated in step (5)
for requiring significant purification following their
synthesis from commercially available reagents.
Claim 7
Dependent Claim
40 words
A process according to any one of claims 1 to 6
wherein in step (12) said revised set of lists of
accessible reagents is selected to include reagents
excluded from the restricted lists generated in step (5)
for being expensive.
Claim 8
Dependent Claim
26 words
A process according to any one of claims 1 to 7
wherein in step (1) said representation is derived from
X-ray crystallographic data for said macromolecule.
Claim 9
Dependent Claim
29 words
A process according to any one of claims 1 to 8
wherein in step (4) said lists of accessible reagents
are generated from a computer database of available
chemicals.
Claim 10
Dependent Claim
29 words
A process according to claim 9 wherein in step (4)
said lists of accessible reagents are supplemented to
include reagents accessible by transformation of
reagents identified from said database.
Claim 11
Dependent Claim
53 words
A process according to any one of claims 1 to 10
wherein the model generated in step (2) comprises a
representation of those regions of the binding site
capable of interaction with a molecule placed in said
binding site the said regions being identified according
to the nature and geometry of said interaction.
Claim 12
Dependent Claim
183 words
A process according to any one of claims 1 to 11
wherein in step (5) said computerised comparison for a
reagent involves in sequence: (i) carrying out a
subgraph isomorphism check to establish a match between
said unique component of said reagent and said
computerised model, (ii) rejecting reagents for which no
match can be found, (iii) verifying the match for non-rejected
reagents by torsional optimization of the
rotatable bonds in the unique component, (iv)
calculating the compatibility between the computerised
model and a structure comprising the molecular fragment
and the substituent deriving from the unique component
of the reagent in the confirmation predicted by step
(iii), (v) optionally repeating steps (iii) and (iv) to
seek a conformation with enhanced compatibility, (vi)
rejecting reagents for which a preselected degree of
compatibility is not found in steps (iv) and (v), (vii)
determining a score indicative of a minimum energy level
for said structure within said computerised model with
the structure and position of said molecular fragment
held constant, and (viii) ranking the reagents in a list
according to the scores determined in step (vii).
Claim 13
Dependent Claim
51 words
A process according to claim 12 wherein in step
(vii) scores indicative of strain energy and
contributions to energy level of individual interactions
of components of said structure with said computerised
model are also determined and reagents are rejected if
such scores exceed pre-selected limits indicative of
undesirable conformation or interaction.
Claim 14
Dependent Claim
16 words
Novel active compounds identified by a process
according to any one of claims 1 to 13.
Claim 15
Independent Claim
606 words
A method of manufacturing a drug substance, said
method comprising the steps of: (1) obtaining a computerised representation of the
three-dimensional structure of a binding site on the
surface of a biological macromolecule; (2) generating a computerised model of the functional
structure of said binding site which may be used to
identify favourable and unfavourable interactions
between the binding site and a drug candidate molecule; (3) identifying a molecular fragment capable of
placement within said binding site and capable of
carrying at least one substituent group, said molecular
fragment either being capable of being synthesized from
reagent compounds accessible in substituted form whereby
to import said substituent groups on synthesis of said
molecular fragment or being present in an accessible
reagent compound capable of substitution with said
substituent groups by reaction with further accessible
reagent compounds; (4) generating a set of lists of accessible reagent
compounds, the lists being such that a combination of
compounds taken from each list may be reacted to produce
a candidate compound comprising said molecular fragment
carrying a plurality of substituent groups thereby
generating a first virtual library of candidate
compounds being the theoretical set of compounds
producible by reaction of the members of said lists,
each member of each list comprising a component common
to the other members of that list and a component unique
within that list; (5) for each said list limiting the number of members
thereof using a first set of exclusion rules thereby to
generate a restricted second virtual library of
candidate compounds, the operation of said first set of
rules involving for each member of each list
computerised comparison for favourable or unfavourable
interactions between said computerised model and a
structure comprising said molecular fragment and a
substituent deriving from the unique component within
said list of that member, the molecular fragment and the
computerised model being held in fixed spatial
relationship to each other for said comparison; (6) evaluating and ranking by computer the members of
said second virtual library for favourable and
unfavourable interactions with said computerised model
and thereby generating a restricted third virtual
library of candidate compounds ranked as having
favourable interactions; (7) optionally, selecting from said third virtual
library at least one further molecular fragment and
repeating steps (4), (5) and (6) to generate an
alternative third virtual library; (8) screening said third virtual library using a second
set of exclusion rules thereby to generate a restricted
fourth virtual library of candidate compounds comprising
compounds which are candidates for synthesis and
experimental evaluation for drug efficacy; (9) synthesizing some or all candidate compounds of
said fourth virtual library to produce a candidate
compound library; (10) experimentally evaluating the compounds of said
candidate compound library for drug efficacy; (11) analysing the experimental efficacy data generated
in step (10) for structure-activity relationship
information; (12) using the information derived in step (11)
selecting a revised set of lists of accessible reagent
compounds, said lists being expanded to include selected
reagents not present in the restricted lists generated
in step (5) and optionally restricted to exclude
selected reagents present in the restricted lists
generated in step (5); (13) repeating steps (6) and (7) to identify further
compounds which are candidates for synthesis and
experimental evaluation for drug efficacy; (14) synthesising and experimentally evaluating said
further compounds for drug efficacy; (15) if required repeating steps (11) to (14) one or
more times; (16) identifying as a lead candidate a compound
synthesized and experimentally evaluated as above; (17) manufacturing the compound identified in step (16)
above; and, optionally, (18) admixing the compound manufactured in step (17)
above with at least one pharmaceutically acceptable
carrier or excipient.