Modulating hydrogen-bond basicity within the context of protein-ligand binding: A case study with thrombin inhibitors that reveals a dominating role for desolvation.
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.
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, 14260, United States; The Division of Pharmaceutical Chemistry, National Organization for Drug Control and Research (NODCAR), Giza, Egypt. Electronic address: nnnasief@yahoo.com.
Nader N
NN
Nasief
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, 14260, United States; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Helwan, Egypt.
Ahmed M
AM
Said
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, 14260, United States. Electronic address: hangauer@buffalo.edu.
David
D
Hangauer
D000818:Animals; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D011485:Protein Binding / Q000187:drug effects; D012997:Solvents / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008024:Ligands; D012997:Solvents; D013917:Thrombin
B3LYP/6-31G(∗); Bioisosterism; Cooperativity; Desolvation; Hydrogen bond; Nonadditivity; Protein-ligand binding; Thrombin