- Modulating hydrogen-bond basicity within the context of protein-ligand binding: A case study with thrombin inhibitors that?reveals a dominating role for desolvation
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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.
- Nasief, Nader N.,Said, Ahmed M.,Hangauer, David
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p. 975 - 991
(2016/11/11)
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- Enhancement of hydrophobic interactions and hydrogen bond strength by cooperativity: Synthesis, modeling, and molecular dynamics simulations of a congeneric series of thrombin inhibitors
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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.
- Muley, Laveena,Baum, Bernhard,Smolinski, Michael,Freindorf, Marek,Heine, Andreas,Klebe, Gerhard,Hangauer, David G.
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supporting information; experimental part
p. 2126 - 2135
(2010/08/19)
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- PS-IIDQ: a supported coupling reagent for efficient and general amide bond formation
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Polystyrene-IIDQ, a polymer-supported coupling reagent, was synthesized in three steps from Merrifield resin in 86% overall conversion. This reagent efficiently coupled carboxylic acids to amines in good yields and high purities, required no pre-activation step, and was tolerant of the order of reagent addition. PS-IIDQ was observed to be more efficient than polymer-supported carbodiimides (PS-EDC and PS-DCC) and gave higher yields than HATU for general amide bond formation, including the coupling of anilines and hindered substrates. When evaluated with five carboxylic acids and nine amines (including anilines and secondary amines) PS-IIDQ gave an average isolated yield of 73%.
- Valeur, Eric,Bradley, Mark
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p. 8855 - 8871
(2008/02/11)
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- 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
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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
- Abraham,Gazze,Kennedy,Mokotoff
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p. 1549 - 1559
(2007/10/02)
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- Tri- and tetrapeptide analogues of kinins as potential renal vasodilators
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Tri- and tetrapeptide analogues were synthesized and evaluated as renal vasodilators. These peptides were prepared by standard coupling reactions which also provided good yields with hindered α-methyl amino acid derivatives. Preliminary evidence of renal vasodilator activity was determined in anesthetized dogs by measuring the effects on renal blood flow and calculating the accompanying changes in renal vascular resistance. The most potent compounds contained, in their structure, the L-prolyl-DL-α-methylphenylalanyl-L-arginine and L-prolyl-DL-α-methyl-phenyalanylglycyl-L-proline arrays. Substitution on the N-terminal proline with 4-phenylbutyryl and 4-(4-hydroxyphenyl)butyryl side chains produced enhanced renal vasodilator activity and, in certain cases, selectivity for the renal vasculature.
- Pfeiffer,Chambers,Hilbert,Woodward,Ackerman
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p. 325 - 341
(2007/10/02)
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