BREED: Generating Novel Inhibitors through Hybridization of Known Ligands. Application to CDK2, P38, and HIV Protease
In this work we describe BREED, a method for the generation of novel inhibitors from structures of known ligands bound to a common target. The method is essentially an automation of the common medicinal chemistry practice of joining fragments of two known ligands to generate a new inhibitor. The lig...
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Veröffentlicht in: | Journal of medicinal chemistry 2004-05, Vol.47 (11), p.2768-2775 |
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creator | Pierce, Albert C Rao, Govinda Bemis, Guy W |
description | In this work we describe BREED, a method for the generation of novel inhibitors from structures of known ligands bound to a common target. The method is essentially an automation of the common medicinal chemistry practice of joining fragments of two known ligands to generate a new inhibitor. The ligand-bound target structures are overlaid, all overlapping bonds in all pairs of ligands are found, and the fragments on each side of each matching bond are swapped to generate the new molecules. Since the method is automated, it can be applied recursively to generate all possible combinations of known ligands. In an application of this method to HIV protease inhibitors and protein kinase inhibitors, hundreds of new molecular structures were generated. These included known inhibitor scaffolds not included in the initial set, entirely novel scaffolds, and novel substituents on known scaffolds. The method is fast, and since all of the ligand functional groups are known to bind the target in the precise position and orientation present in the novel ligand, the success rate of this method should be superior to more traditional de novo design techniques. In an era of increasingly high-throughput structural biology, such methods for high-throughput utilization of structural information will become increasingly valuable. |
doi_str_mv | 10.1021/jm030543u |
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In an application of this method to HIV protease inhibitors and protein kinase inhibitors, hundreds of new molecular structures were generated. These included known inhibitor scaffolds not included in the initial set, entirely novel scaffolds, and novel substituents on known scaffolds. The method is fast, and since all of the ligand functional groups are known to bind the target in the precise position and orientation present in the novel ligand, the success rate of this method should be superior to more traditional de novo design techniques. In an era of increasingly high-throughput structural biology, such methods for high-throughput utilization of structural information will become increasingly valuable.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm030543u</identifier><identifier>PMID: 15139755</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Biological and medical sciences ; Crystallization ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins - antagonists & inhibitors ; Cyclins - chemistry ; Enzyme Inhibitors - chemistry ; HIV Protease - chemistry ; HIV Protease Inhibitors - chemistry ; Ligands ; Medical sciences ; Miscellaneous ; Mitogen-Activated Protein Kinases - antagonists & inhibitors ; Mitogen-Activated Protein Kinases - chemistry ; Models, Molecular ; Molecular Structure ; p38 Mitogen-Activated Protein Kinases ; Pharmacology. 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Application to CDK2, P38, and HIV Protease</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>In this work we describe BREED, a method for the generation of novel inhibitors from structures of known ligands bound to a common target. The method is essentially an automation of the common medicinal chemistry practice of joining fragments of two known ligands to generate a new inhibitor. The ligand-bound target structures are overlaid, all overlapping bonds in all pairs of ligands are found, and the fragments on each side of each matching bond are swapped to generate the new molecules. Since the method is automated, it can be applied recursively to generate all possible combinations of known ligands. In an application of this method to HIV protease inhibitors and protein kinase inhibitors, hundreds of new molecular structures were generated. These included known inhibitor scaffolds not included in the initial set, entirely novel scaffolds, and novel substituents on known scaffolds. The method is fast, and since all of the ligand functional groups are known to bind the target in the precise position and orientation present in the novel ligand, the success rate of this method should be superior to more traditional de novo design techniques. In an era of increasingly high-throughput structural biology, such methods for high-throughput utilization of structural information will become increasingly valuable.</description><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Biological and medical sciences</subject><subject>Crystallization</subject><subject>Cyclin-Dependent Kinase Inhibitor p21</subject><subject>Cyclins - antagonists & inhibitors</subject><subject>Cyclins - chemistry</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>HIV Protease - chemistry</subject><subject>HIV Protease Inhibitors - chemistry</subject><subject>Ligands</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Mitogen-Activated Protein Kinases - antagonists & inhibitors</subject><subject>Mitogen-Activated Protein Kinases - chemistry</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>p38 Mitogen-Activated Protein Kinases</subject><subject>Pharmacology. 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Application to CDK2, P38, and HIV Protease</title><author>Pierce, Albert C ; Rao, Govinda ; Bemis, Guy W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a379t-a0ddb4850aeb54aca80eaf33fe80fb19fe69aed7b8ec29cbbbc4102e83ec2aee3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Biological and medical sciences</topic><topic>Crystallization</topic><topic>Cyclin-Dependent Kinase Inhibitor p21</topic><topic>Cyclins - antagonists & inhibitors</topic><topic>Cyclins - chemistry</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>HIV Protease - chemistry</topic><topic>HIV Protease Inhibitors - chemistry</topic><topic>Ligands</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>Mitogen-Activated Protein Kinases - antagonists & inhibitors</topic><topic>Mitogen-Activated Protein Kinases - chemistry</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>p38 Mitogen-Activated Protein Kinases</topic><topic>Pharmacology. Drug treatments</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pierce, Albert C</creatorcontrib><creatorcontrib>Rao, Govinda</creatorcontrib><creatorcontrib>Bemis, Guy W</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pierce, Albert C</au><au>Rao, Govinda</au><au>Bemis, Guy W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BREED: Generating Novel Inhibitors through Hybridization of Known Ligands. Application to CDK2, P38, and HIV Protease</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2004-05-20</date><risdate>2004</risdate><volume>47</volume><issue>11</issue><spage>2768</spage><epage>2775</epage><pages>2768-2775</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>In this work we describe BREED, a method for the generation of novel inhibitors from structures of known ligands bound to a common target. The method is essentially an automation of the common medicinal chemistry practice of joining fragments of two known ligands to generate a new inhibitor. The ligand-bound target structures are overlaid, all overlapping bonds in all pairs of ligands are found, and the fragments on each side of each matching bond are swapped to generate the new molecules. Since the method is automated, it can be applied recursively to generate all possible combinations of known ligands. In an application of this method to HIV protease inhibitors and protein kinase inhibitors, hundreds of new molecular structures were generated. These included known inhibitor scaffolds not included in the initial set, entirely novel scaffolds, and novel substituents on known scaffolds. The method is fast, and since all of the ligand functional groups are known to bind the target in the precise position and orientation present in the novel ligand, the success rate of this method should be superior to more traditional de novo design techniques. In an era of increasingly high-throughput structural biology, such methods for high-throughput utilization of structural information will become increasingly valuable.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>15139755</pmid><doi>10.1021/jm030543u</doi><tpages>8</tpages></addata></record> |
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subjects | Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Biological and medical sciences Crystallization Cyclin-Dependent Kinase Inhibitor p21 Cyclins - antagonists & inhibitors Cyclins - chemistry Enzyme Inhibitors - chemistry HIV Protease - chemistry HIV Protease Inhibitors - chemistry Ligands Medical sciences Miscellaneous Mitogen-Activated Protein Kinases - antagonists & inhibitors Mitogen-Activated Protein Kinases - chemistry Models, Molecular Molecular Structure p38 Mitogen-Activated Protein Kinases Pharmacology. Drug treatments Structure-Activity Relationship |
title | BREED: Generating Novel Inhibitors through Hybridization of Known Ligands. Application to CDK2, P38, and HIV Protease |
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