Binding kinetics in drug discovery - A current perspective.
The impact of target binding kinetics (BK) on the clinical performance of therapeutic agents is presently a topic of intense debate in drug discovery. While retrospective studies suggest that BK is a differentiating parameter in marketed medicines, it is yet unclear how this information could be used to prioritize drug candidates during lead optimization. Motivated by the question whether BK can be understood and rationally optimized, we review the most relevant literature in the field, with special focus on selected examples from our organization. First we discuss structure-kinetic relationships (SKR), and how they can be influenced by factors such as conformational changes, molecular flexibility, hydrogen bonds, hydrophobicity, water molecules and (reversible-) covalent bonds. We then introduce the methodologies currently used for the investigation of BK parameters, briefly commenting on their strengths, weaknesses and future trends. Finally, we present our current perspective on the integration of BK in the drug discovery process, aiming to stimulate further thoughts on this important subject.
Bayer Pharma AG, Lead Discovery Berlin, Muellerstrasse 178, 13353 Berlin, Germany.
Victoria
V
Georgi
Bayer Pharma AG, Lead Discovery Berlin, Muellerstrasse 178, 13353 Berlin, Germany.
Dorothee
D
Andres
Bayer Pharma AG, Lead Discovery Berlin, Muellerstrasse 178, 13353 Berlin, Germany.
Amaury E
AE
Fernandez-Montalvan
Bayer Pharma AG, Lead Discovery Berlin, Muellerstrasse 178, 13353 Berlin, Germany.
Christian M
CM
Stegmann
Bayer Pharma AG, Lead Discovery Berlin, Muellerstrasse 178, 13353 Berlin, Germany.
Andreas
A
Becker
Bayer Pharma AG, Lead Discovery Berlin, Muellerstrasse 178, 13353 Berlin, Germany, anke.mueller-fahrnow@bayer.com.
Anke
A
Mueller-Fahrnow
D000818:Animals; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008024:Ligands; D008968:Molecular Conformation; D009536:Niacinamide / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D010671:Phenylurea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000737:chemistry; D000077157:Sorafenib; D013329:Structure-Activity Relationship
C553185:DFG peptide; D008024:Ligands; D009842:Oligopeptides; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; D019908:Proto-Oncogene Proteins c-raf