3D-RISM-Dock: A New Fragment-Based Drug Design Protocol

Abstract

We explore a new approach in the rational design of specificity in molecular recognition of small molecules based on statistical-mechanical integral equation theory of molecular liquids in the form of the three-dimensional reference interaction site model with the Kovalenko-Hirata closure (3D-RISM-KH). The numerically stable iterative solution of conventional 3D-RISM equations includes the fragmental decomposition of flexible ligands, which are treated as distinct species in solvent mixtures of arbitrary complexity. The computed density functions for solution (including ligand) molecules are obtained as a set of discrete spatial grids that uniquely describe the continuous solvent-site distribution around the protein solute. Potentials of mean force derived from these distributions define the scoring function interfaced with the AutoDock program for an automated ranking of docked conformations. As a case study in terms of solvent composition, we analyze cooperative interactions encountered in the binding of a flexible thiamine molecule to the prion protein at near-physiological conditions. The predicted location and residency times of computed binding modes are in excellent agreement with the available experimental data.

Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description

“…Similar conclusions were also drawn by Hritz et al [144]. The only solution still relies in a deep knowledge of the dataset to be screened, and of the target or of related known proteins, and in an improvement of the currently available scoring functions [21,263,264].…”

Role of Water in Ligand Binding to Maltose-Binding Protein: Insight from a New Docking Protocol Based on the 3D-RISM-KH Molecular Theory of Solvation

“…Such polarization of the water site densities are clearly seen around the polar residues of MBP ( Figure 3 The 3D-RISM-KH solvent densities can be directly incorporated into the docking protocol to describe the desolvation effects upon ligand binding. 71 Also, locations of tightly bound water molecules can be predicted based on the 3D-RISM-KH densities, 49−51 and these explicit water molecules can be used in conventional docking simulations. In this section, we find locations of explicit water molecules at the apo-open state of MBP by using the protocol described in Computational Methods section.…”

Water-mediated forces between the nucleotide binding domains generate the power stroke in an ABC transporter

“…The 3D-RISM theory is a statistical mechanics theory of molecular liquids [15][16][17][18], which is successfully applied to a variety of biological processes [19][20][21][22][23][24][25][26][27][28][29][30][31].…”