92010-16-7Relevant academic research and scientific papers
Modulating hydrogen-bond basicity within the context of protein-ligand binding: A case study with thrombin inhibitors that?reveals a dominating role for desolvation
Nasief, Nader N.,Said, Ahmed M.,Hangauer, David
, p. 975 - 991 (2016/11/11)
Understanding subtle aspects of hydrogen bonding is a challenging but crucial task to improve our ability to design ligands with high affinity for protein hosts. To gain a deeper understanding of these aspects, we investigated a series of thrombin inhibitors in which the basicity of the ligand's group that accepts an H-bond from Gly216 was modulated via bioisosterism; e.g., a C=O acceptor was made electron deficient or rich via bioisosteric replacements of the adjacent moiety. Although the ligand's binding affinity was anticipated to improve when the H-bond basicity is increased (due to stronger H-bonding with the protein), we herein present data that unexpectedly revealed an opposite trend. This trend was attributed to a dominating role played by desolvation in determining the relative binding affinity. For example, a decrease in the H-bond basicity reduces the desolvation penalty and, as experimentally observed, improves the binding affinity, given that the reduction in the desolvation penalty dominates the change in the net contribution of the ligand's interactions with the protein. The current study, therefore, reveals that desolvation can be a major underlying cause for the apparently counterintuitive structure-activity relationship (SAR) outcomes, and indicates that understanding this factor can improve our ability to predict binding affinity and to design more potent ligands.
Enhancement of hydrophobic interactions and hydrogen bond strength by cooperativity: Synthesis, modeling, and molecular dynamics simulations of a congeneric series of thrombin inhibitors
Muley, Laveena,Baum, Bernhard,Smolinski, Michael,Freindorf, Marek,Heine, Andreas,Klebe, Gerhard,Hangauer, David G.
supporting information; experimental part, p. 2126 - 2135 (2010/08/19)
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 ?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 ?2 demonstrates cooperativity between the hydrophobic interaction and the hydrogen bond.
Design, synthesis, and testing of potential antisickling agents. 5. Disubstituted benzoic acids designed for the donor site and proline salicylates designed for the acceptor site
Abraham,Gazze,Kennedy,Mokotoff
, p. 1549 - 1559 (2007/10/02)
This paper reports the discovery of a new class of potent antigelling agents. The new compounds, disubstituted benzoic acid derivatives, were designed by using molecular modeling experiments. These molecules contain functional groups positioned to interac
