MORPH: a new tool for ligand design.
A frequently employed strategy in drug discovery efforts is to replace aromatic rings in known active compounds with alternative aromatic moieties to create novel compounds with improved potency and/or adsorption, distribution, metabolism, excretion, and toxicity properties. Here we introduce MORPH, which is a simple software tool for systematically modifying aromatic rings in three-dimensional models of molecules without altering the coordinates of the nonhydrogen atoms in the rings. MORPH works on individual rings as well as fused ring systems and additionally provides the ability to filter out modified compounds which do not contain hydrogen-bond donors or acceptors at specific positions on the rings or contain more or less than the desired number of heteroatoms. The MORPH program and its application to two ligands extracted from cocrystal structures with cyclin-dependent kinase 2 (CDK2)/cyclin A and CDK2 are discussed below.
Beno
Brett R
BR
Computer-Assisted Drug Design Department, Applied Biotechnology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. Brett.Beno@bms.com
Langley
David R
DR
D000465:Algorithms; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012984:Software
C436945:3-aminopyrazole; D019925:Cyclin A; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D051357:Cyclin-Dependent Kinase 2