Gyrase inhibitors and uses thereof

A bacterial DNA gyrase inhibitor, said inhibitor when bound to the ATP site of a bacterial DNA gyrase B subunit comprises the following features:

• (a) HBA, (b) HBD, (c) at least one feature selected from Grp1 or Grp1a, and (d) at least two features selected from Grp2, Grp3 or Grp4 wherein:
• HBA is a hydrogen bond acceptor;
• HBD is a hydrogen bond donor;
• Grp1 is a chemical moiety having a buried non-polar surface area in the range of about 30-250 (Å)2 and a buried polar surface area in the range of about 40-160 (Å)2;
• Grp1a is a chemical moiety having a buried non-polar surface area in the range of about 35-260 (Å)2 and a buried polar surface area in the range of about 0-110 (Å)2;
• Grp2 is a chemical moiety having a buried non-polar surface area in the range of about 50-300 (Å)2 and a buried polar surface area in the range of about 0-150 (Å)2;
• Grp3 is a chemical moiety having a buried non-polar surface area in the range of about 215-500 (Å)2 and a buried polar surface area in the range of about 25-140 (Å)2;
• Grp4 is a chemical moiety having a buried non-polar surface area in the range of about 150-350 (Å)2 and a buried polar surface area in the range of about 0-100 (Å)2, provided that Grp4 is other than a coumarin ring;
• and
• the distances in angstroms between the features are in the following ranges:
• 8 HBA HBD Grp1 Grp1a Grp2 Grp3 HBA — HBD 0-4.0 — Grp1 2.9-6.4 1.8-5.0 — Grp1a 3.0-8.5 1.8-7.5 0-6.0 — Grp2 3.0-6.3 2.8-6.4 2.3-7.8 2.3-6.5 — Grp3 1.8-7.0 2.7-7.5 3.5-9.5 3.5- 2.2-6.6 — 11.0 Grp4 5.0-9.1 6.3- 7.4- 7.5- 5.8- 1.9-9.0 10.3 15.0 16.0 10.0

A method of treating a bacterial infection in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a bacterial DNA gyrase inhibitor, said inhibitor capable of forming an enzyme-inhibitor complex comprising a bacterial DNA gyrase and the inhibitor, wherein the complexed inhibitor comprises the following features:

• (a) HBA, (b) HBD, (c) at least one feature selected from Grp1 or Grp1a, and (d) at least two features selected from Grp2, Grp3 or Grp4 wherein:
• HBA is a hydrogen bond acceptor;
• HBD is a hydrogen bond donor;
• Grp1 is a chemical moiety having a buried non-polar surface area in the range of about 30-250 (Å)2 and a buried polar surface area in the range of about 40-160 (Å)2;
• Grp1a is a chemical moiety having a buried non-polar surface area in the range of about 35-260 (Å)2 and a buried polar surface area in the range of about 0-110 (Å)2;
• Grp2 is a chemical moiety having a buried non-polar surface area in the range of about 50-300 (Å)2 and a buried polar surface area in the range of about 0-150 (Å)2;
• Grp3 is a chemical moiety having a buried non-polar surface area in the range of about 215-500 (Å)2 and a buried polar surface area in the range of about 25-140 (Å)2;
• Grp4 is a chemical moiety having a buried non-polar surface area in the range of about 150-350 (Å)2 and a buried polar surface area in the range of about 0-100 (Å)2, provided that Grp4 is other than a coumarin ring;
• and
• the distances in angstroms between the features are in the following ranges:
• 9 HBA HBD Grp1 Grp1a Grp2 Grp3 HBA — HBD 0-4.0 — Grp1 2.9-6.4 1.8-5.0 — Grp1a 3.0-8.5 1.8-7.5 0-6.0 — Grp2 3.0-6.3 2.8-6.4 2.3-7.8 2.3-6.5 — Grp3 1.8-7.0 2.7-7.5 3.5-9.5 3.5- 2.2-6.6 — 11.0 Grp4 5.0-9.1 6.3- 7.4- 7.5- 5.8- 1.9-9.0 10.3 15.0 16.0 10.0

A method of designing a bacterial DNA gyrase inhibitor comprising the steps of:

• (a) providing a first structure that comprises HBA, HBD, and zero to four features selected from Grp1, Grp1a, Grp2, Grp3, or Grp4, and
• (b) modifying the first structure to provide a gyrase inhibitor comprising the features present in the first structure and at least one additional feature not present in the first structure and selected from Grp1, Grp1a, Grp2, Grp3, or Grp4;
• wherein the gyrase inhibitor comprises the following features:
• (a) HBA, (b) HBD, (c) at least one feature selected from Grp1 or Grp1a, and (d) at least two features selected from Grp2, Grp3 or Grp4;
• HBA is a hydrogen bond acceptor and HBD is a hydrogen bond donor;
• Grp1 is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area in the range of about 30-250 (Å)2 and a buried polar surface area in the range of about 40-160 (Å)2;
• Grp1a is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area in the range of about 35-260 (Å)2 and a buried polar surface area in the range of about 0-110 (Å)2;
• Grp2 is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area in the range of about 50-300 (Å)2 and a buried polar surface area in the range of about 0-150 (Å)2;
• Grp3 is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area in the range of about 215-500 (Å)2 and a buried polar surface area in the range of about 25-140 (Å)2;
• Grp4 is a chemical moiety which, when bound to the ATP binding site of a bacterial DNA gyrase, has a buried non-polar surface area in the range of about 150-350 (Å)2 and a buried polar surface area in the range of about 0-100 (Å)2, provided that Grp4 is other than a coumarin ring;
• and
• the distances in angstroms between the features are in the following ranges:
• 10 HBA HBD Grp1 Grp1a Grp2 Grp3 HBA — HBD 0-4.0 — Grp1 2.9-6.4 1.8-5.0 — Grp1a 3.0-8.5 1.8-7.5 0-6.0 — Grp2 3.0-6.3 2.8-6.4 2.3-7.8 2.3-6.5 — Grp3 1.8-7.0 2.7-7.5 3.5-9.5 3.5- 2.2-6.6 — 11.0 Grp4 5.0-9.1 6.3- 7.4- 7.5- 5.8- 1.9-9.0 10.3 15.0 16.0 10.0

A method of determining whether a compound inhibits bacterial DNA gyrase, said method comprising the steps of:

• (a) determining whether the compound comprises an HBA/HBD pair wherein there is one to four bonds separating HBA and HBD;
• (b) docking a three-dimensional structure of the compound into the ATP binding site of bacterial DNA gyrase subunit B such that the HBA/HBD moiety such that (i) HBD is capable of forming a direct hydrogen bond with one or both of the side chain carboxyl oxygens of Asp81 and (ii) HBA is capable of forming a water-bridged hydrogen bond with the side chain carboxyl oxygens of Asp81 and is in the vicinity of the sidechain oxygen of Thr173;
• (c) determining whether the constrained structure from step (b) further comprises at least one feature selected from Grp1 or Grp1a and at least two features selected from Grp2, Grp3 or Grp4;
• and
• (d) determining whether said features, if present, are within suitable distances of each other and the HBA/HBD groups and are capable of forming suitable binding interactions in the gyrB binding site.

A method of designing a new bacterial DNA gyrase inhibitor comprising the steps of:

• (a) providing a molecular fragment comprising an HBA/HBD moiety wherein HBA and HBD are separated by up to 4.0 Å;
• (b) constraining the HBA/HBD moiety within the gyrB ATP site so that (i) HBD is capable of forming a direct hydrogen bond with one or both of the side chain carboxyl oxygens of Asp81 and (ii) HBA is capable of forming a water-bridged hydrogen bond with the side chain carboxyl oxygens of Asp81 and is in the vicinity of the sidechain oxygen of Thr173;
• (c) providing a molecular fragment possessing at least one of Grp1 or Grp1a features, and molecular fragments each possessing at least one of the Grp2, Grp3 or Grp4 features such that at least two of these features are represented among the fragments;
• and
• (d) connecting the fragments selected in step (3) to form a compound comprised of the following features:
• (a) HBA, (b) HBD, (c) at least one feature selected from Grp1 or Grp1a, and (d) at least two features selected from Grp2, Grp3 or Grp4.