Enhancement of hydrophobic interactions and hydrogen bond strength by cooperativity: synthesis, modeling, and molecular dynamics simulations of a congeneric series of thrombin inhibitors.
Accurately predicting the binding affinity of ligands to their receptors by computational methods is one of the major challenges in structure-based drug design. One of the potentially significant errors in these predictions is the common assumption that the ligand binding affinity contributions of noncovalent interactions are additive. Herein we present data obtained from two separate series of thrombin inhibitors containing hydrophobic side chains of increasing size that bind in the S3 pocket and with, or without, an adjacent amine that engages in a hydrogen bond with Gly 216. The first series of inhibitors has a m-chlorobenzyl moiety binding in the S1 pocket, and the second has a benzamidine moiety. When the adjacent hydrogen bond is present, the enhanced binding affinity per A(2) of hydrophobic contact surface in the S3 pocket improves by 75% and 59%, respectively, over the inhibitors lacking this hydrogen bond. This improvement of the binding affinity per A(2) demonstrates cooperativity between the hydrophobic interaction and the hydrogen bond.
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, USA.
Laveena
L
Muley
Bernhard
B
Baum
Michael
M
Smolinski
Marek
M
Freindorf
Andreas
A
Heine
Gerhard
G
Klebe
David G
DG
Hangauer
D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000502:physiology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D015842:Serine Proteinase Inhibitors; D013917:Thrombin