METHODS FOR IDENTIFYING COMPOUNDS
The present disclosure provides virtual screening methods utilizing data sets from nucleotide-encoded libraries (e.g., DNA-encoded libraries). These methods allow for high confidence predictions of binding interactions between candidate compounds and proteins of interest useful for the development of therapeutics.
1 . A method comprising the steps of:
(a) providing a plurality of binding interaction findings for a target protein in a physical computing device having a representation of a set of candidate compounds,
wherein at least 90% of the binding interaction findings in the plurality are representative of a binding interaction between the target protein and a compound comprising a nucleotide tag encoding the identity of the compound;
(b) using the computing device to generate estimated binding interactions of the candidate compounds using the plurality of binding interaction findings; and
(c) outputting a candidate compound list capable of being displayed and ranked by highest estimated binding interactions.
2 . The method of claim 1 , wherein the plurality of binding interaction findings comprises at least one million binding interaction findings.
3 . The method of claim 1 , wherein at least 95% of the binding interaction findings in the plurality are representative of a binding interaction between the target protein and a compound comprising a nucleotide tag encoding the identity of the compound.
4 . The method of claim 1 , wherein at least 99% of the binding interaction findings in the plurality are representative of a binding interaction between the target protein and a compound comprising a nucleotide tag encoding the identity of the compound.
5 . The method of claim 1 , wherein at least 50% of the plurality of binding interaction findings were determined by contacting a plurality of compounds comprising a nucleotide tag encoding the identity of the compound with a target protein simultaneously.
6 . The method of claim 1 , wherein the method further comprises providing one or more additional pluralities of binding interaction findings for one or more additional target proteins, wherein at least 50% of the binding interaction findings in the plurality are representative of a binding interaction between the additional target protein and a compound from the plurality of binding interactions with the target protein.
7 . The method of claim 6 , wherein the candidate compound list is capable of being displayed and ranked by the selectivity of the candidate compound for the target protein over the one or more additional target proteins.
8 . The method of claim 6 , wherein the one or more additional target proteins comprise a mutant of the target protein.
9 . The method of claim 1 , wherein the method further comprises providing one or more additional pluralities of binding interaction findings for one or more negative control experiments, wherein at least 50% of the binding interaction findings in the plurality are representative of a negative control experiment of a compound from the plurality of binding interactions with the target protein.
10 . The method of claim 1 , wherein the method further comprises transmitting the candidate compound list over the internet or to a display device.
11 . The method of claim 1 , wherein the physical computing device is accessed and operated over the internet.
12 . The method of claim 1 , wherein the estimated binding interactions are generated using chemical structure comparisons.
13 . The method of claim 12 , wherein the chemical structure comparison utilizes molecular representations.
14 . The method of claim 13 , wherein the molecular representations comprise chemical fingerprints.
15 . The method of claim 14 , wherein the chemical fingerprint analysis is FCFP6, FCFP6, FCFP4, MACCS, or Morgan/Circular Fingerprints.
16 . The method of claim 1 , wherein the method further comprises generating a believability score for each of the estimated binding interactions of the candidate compounds, wherein the believability score is generated using chemical structure comparisons of the candidate compound and one or more compounds from the plurality of binding interactions for the target protein.
17 . The method of claim 16 , wherein the chemical structural comparison is principal component analysis.
18 . The method of claim 16 , wherein the candidate compound list is capable of being displayed and ranked by the believability score of the estimated binding interaction for the candidate compound.
19 . The method of claim 1 , wherein the method further comprises providing a one or more property findings for the set of candidate compounds.
20 . The method of claim 19 , wherein the one or more property findings include molecular weight and/or clog P.
21 . The method of claim 19 , wherein the one or more property findings are utilized to generate the estimated binding interactions.
22 . The method of claim 19 , wherein the candidate compound list is capable of being displayed and ranked by the one or more property findings.
23 . The method of claim 1 , wherein the method further comprises (d) synthesizing one or more of the candidate compounds from the candidate compound list.
24 . The method of claim 23 , wherein the method further comprises contacting the one or more synthesized candidate compounds with the target protein to determine one or more experimental binding interactions.
25 . A computer readable medium having stored thereon executable instructions for directing a physical computing device to implement a method comprising the steps of:
(a) providing a plurality of binding interaction findings for a target protein in a physical computing device having a representation of a set of candidate compounds,
wherein at least 90% of the binding interaction findings in the plurality are representative of a binding interaction between the target protein and a compound comprising a nucleotide tag encoding the identity of the compound;
(b) using the computing device to generate estimated binding interactions of the candidate compounds using the plurality of binding interaction findings; and
(c) outputting a candidate compound list capable of being displayed and ranked by highest estimated binding interactions.
26 . A physical computing device having a representation of a set of candidate compounds and programmed with executable instructions for directing the device to implement a method comprising the steps of:
(a) providing a plurality of binding interaction findings for a target protein in a physical computing device having a representation of a set of candidate compounds,
wherein at least 90% of the binding interaction findings in the plurality are representative of a binding interaction between the target protein and a compound comprising a nucleotide tag encoding the identity of the compound;
(b) using the computing device to generate estimated binding interactions of the candidate compounds using the plurality of binding interaction findings; and
(c) outputting a candidate compound list capable of being displayed and ranked by highest estimated binding interactions.