RETRACTED: Packing defects as selectivity switches for drug-based protein inhibitors

Abstract

The conservation of structure across homolog proteins often diffuses the impact of drug-based inhibition by promoting alternative protein-ligand associations that may lead to toxic side effects. However, sticky packing defects are typically not conserved across homologs, making them valuable a priori targets to enhance specificity. By introducing a homology to quantify packing differences among proteins, we enable a previously undescribed strategy for the design of highly selective drug inhibitors involving ligands that wrap nonconserved packing defects. The selectivity of these ligands is validated by performing affinity assays on a cancer-related pharmacokinome. Minor reengineering of a powerful inhibitor guided by wrapping differences across its target kinome can selectively direct its impact toward a specific kinase. Thus, nonconserved packing defects may be used as selectivity switches across homolog targets, using spatial displacements of packing defects across aligned protein structures.

Hydration Profiles of Amyloidogenic Molecular Structures

“…f is related to the size of the protein surface area bearing structural defects, which can be estimated from molecular simulations [9,12,[15][16][17][18]. Normally, association of proteins in soluble oligomers squeezes patches of bulk-like waters from the interacting surfaces.…”

“…Therefore, structural alterations of cellular proteins change the distribution and dynamics of surrounding water molecules. Recent studies [9,12] suggest that proteins bearing pathological defects, i.e., proteins exhibiting poorly dehydrated backbone H bonds (dehydrons) [15][16][17][18], are characterized by an average energy of hydration which is significantly below that corresponding to native proteins. The entropy of water next to these structural defects is unexpectedly large and much shorter than at the other surface sites [9].…”

Dehydration Propensity of Order−Disorder Intermediate Regions in Soluble Proteins

“…The structural integrity of a soluble protein is contingent on its capacity to exclude water from its amide-carbonyl hydrogen bonds. , Water-exposed intramolecular hydrogen bonds in native folds constitute structural singularities representing packing defects that have been recently characterized. − In turn, these defects favor the removal of surrounding water as a means to strengthen and stabilize the underlying electrostatic interaction, and thus are implicated in protein associations and macromolecular recognition. − ,− The strength and stability of deficiently packed hydrogen bondsthe so-called dehydrons 5,6 may be modulated by an external agent. More precisely, intramolecular hydrogen bonds which are not “wrapped” by a sufficient number of nonpolar groups may become stabilized and strengthened by the attachment of a ligand or binding partner that further contributes to their dehydration. − The net gain in Coulomb energy associated with wrapping a dehydron has been experimentally determined to be ∼4 kJ/mol . The adhesive force exerted by a dehydron on a hydrophobe at 6 Å distance is ∼7.8 pN, a magnitude comparable to the hydrophobic attraction between two nonpolar moieties that frame unfavorable interfaces with water .…”

“…1,2 Water-exposed intramolecular hydrogen bonds in native folds constitute structural singularities representing packing defects that have been recently characterized. [2][3][4][5][6][7] In turn, these defects favor the removal of surrounding water as a means to strengthen and stabilize the underlying electrostatic interaction, and thus are implicated in protein associations and macromolecular recognition. [2][3][4][5][8][9][10][11][12][13] The strength and stability of deficiently packed hydrogen bondssthe so-called dehydrons 5,6 smay be modulated by an external agent.…”

“…More precisely, intramolecular hydrogen bonds which are not "wrapped" by a sufficient number of nonpolar groups may become stabilized and strengthened by the attachment of a ligand or binding partner that further contributes to their dehydration. [2][3][4][5][6][7][8][9][10][11] The net gain in Coulomb energy associated with wrapping a dehydron has been experimentally determined to be ∼4 kJ/ mol. 3 The adhesive force exerted by a dehydron on a hydrophobe at 6 Å distance is ∼7.8 pN, a magnitude comparable to the hydrophobic attraction between two nonpolar moieties that frame unfavorable interfaces with water.…”