The potency–insolubility conundrum in pharmaceuticals: Mechanism and solution for hepatitis C protease inhibitors

Abstract

As compounds are optimized for greater potency during pharmaceutical discovery, their aqueous solubility often decreases, making them less viable as orally-administered drugs. To investigate whether potency and insolubility share a common origin, we examined the structural and thermodynamic properties of telaprevir, a sparingly soluble inhibitor of hepatitis C virus protease. Comparison of the hydrogen bond motifs in crystalline telaprevir with those present in the protease-telaprevir complex revealed striking similarities. Additionally, the thermodynamics of telaprevir dissolution closely resembles those of protein-ligand dissociation. Together, these findings point to a common origin of potency and insolubility rooted in particular amide-amide hydrogen bond patterns. The insolubility of telaprevir is shown by computational analysis to be caused by interactions in the crystal, not unfavorable hydrophobic hydration. Accordingly, competing out the particular amide-amide hydrogen bond motifs in crystalline telaprevir with 4-hydroxybenzoic acid yielded a co-crystalline solid with excellent aqueous dissolution and oral absorption. The analysis suggests a generalizable approach for identifying drug candidate compounds that either can or cannot be rendered orally bioavailable by alteration of their crystalline solid phases, in an approach that provides a pragmatic way to attain substantial enhancements in the success rate of drug discovery and development.

Computational and In Vitro Investigation of (-)-Epicatechin and Proanthocyanidin B2 as Inhibitors of Human Matrix Metalloproteinase 1

“…Moreover, electrostatic interactions like in heteroatom-hydrogen bonds X-H···Y (X = O or N; Y = O, N, or halogen), salt bridges, van der Waals interactions (π-π interactions), carbon–hydrogen, and metal interactions are required for the formation and stability of the protein–ligand complexes [ 68 , 69 , 70 ]. Especially, hydrogen bond is observed as an intermolecular interaction that exhibits covalent, electrostatic, and van der Waals properties [ 71 , 72 ] Therefore, hydrogen bonds not only mediate protein–ligand binding but also influence the physicochemical properties of the molecules, such as solubility, distribution, partitioning, and permeability, which are key characteristics for drug development [ 73 , 74 ]. Typically, in protein–ligand complex, hydrogen bond formation such as C = O···H, N–H···O, O–H···O, and N–H···N are classified as strong bonds because of presence of highly electronegative atoms, i.e., Nitrogen (N) and Oxygen (O), while weak bonds such as C–H···O and C–H···N are categorized as the most common type of intermolecular hydrogen bond formation between the protein and ligand [ 75 ].…”

“…For instance, in the MMP-1-(-)-epicatechin complex, hydroxy groups on the 3,4-dihydro-2Hchromene-3,5,7-triol ring exhibited strong and moderate donor hydrogen bonds with residues Ala182 Moreover, electrostatic interactions like in heteroatom-hydrogen bonds X-H•••Y (X = O or N; Y = O, N, or halogen), salt bridges, van der Waals interactions (π-π interactions), carbon-hydrogen, and metal interactions are required for the formation and stability of the protein-ligand complexes [68][69][70]. Especially, hydrogen bond is observed as an intermolecular interaction that exhibits covalent, electrostatic, and van der Waals properties [71,72] Therefore, hydrogen bonds not only mediate protein-ligand binding but also influence the physicochemical properties of the molecules, such as solubility, distribution, partitioning, and permeability, which are key characteristics for drug development [73,74]. Typically, in protein-ligand complex, hydrogen bond formation such as [75].…”

Optimizing Electrostatic Similarity for Virtual Screening: A New Methodology

“…This software has been downloaded without modification from the original website (Open-Eye Scientific Software, 2019c). It is worth mentioning that ROCS and ZAP are, by far, the most widely used tools in the literature for VS based on shape and electrostatic similarity (Ellingson et al, 2010;Thomas et al, 2013;Hawkins and Stahl, 2018;Connelly et al, 2015;Gowthaman et al, 2015). For this reason they have been selected as part of this study; i.e.…”

Structure-Based Identification of Natural Products as SARS-CoV-2 Mpro Antagonist from Echinacea angustifolia Using Computational Approaches

“…In molecular docked complexes, non-covalent interaction, such as electrostatic interactions, van der Waals interactions, salt bridges, hydrogen bonding, and metal interactions, are known to play a key role in the formation and stability of the receptor-ligand complex [58,59]. Remarkably, hydrogen bonding was reported to mediate the ligand binding with the receptor and fundamentally contribute to the physiochemical properties of the molecules, which are essentially required for the drug development of lead compounds [60,61]. Thus, each docked complex of natural products with SARS-CoV-2 M pro was studied for intermolecular interactions at 4 Å distance around the ligand with default parameters using the 2D interaction tool in Maestro-Schrödinger suite (Figure 4).…”