Binding mode information improves fragment docking

<div>Accurately predicting protein-ligand binding is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation timescales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes.</div><div><br></div><div>In this technique the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over two orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step towards applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding Modes of Ligands using Enhanced Sampling (BLUES) package which is freely available on GitHub.</div>

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Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes Using Nonequilibrium Candidate Monte Carlo

10.26434/chemrxiv.5406907 ◽

2018 ◽

Author(s):

Samuel Gill ◽

Nathan M. Lim ◽

Patrick Grinaway ◽

Ariën S. Rustenburg ◽

Josh Fass ◽

...

Keyword(s):

Monte Carlo ◽

Ligand Binding ◽

Binding Mode ◽

Free Energy Calculations ◽

Dynamics Simulation ◽

Binding Modes ◽

Enhanced Sampling ◽

Recent Success ◽

Multiple Binding ◽

Proper Sampling

<div>Accurately predicting protein-ligand binding is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation timescales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes.</div><div><br></div><div>In this technique the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over two orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step towards applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding Modes of Ligands using Enhanced Sampling (BLUES) package which is freely available on GitHub.</div>

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D3R Grand Challenge 4: Ligand Similarity and MM-GBSA-Based Pose Prediction and Affinity Ranking for BACE-1 Inhibitors

10.26434/chemrxiv.8259074.v1 ◽

2019 ◽

Author(s):

Sukanya Sasmal ◽

Léa El Khoury ◽

David Mobley

Keyword(s):

Binding Mode ◽

Energy Estimates ◽

Poor Correlation ◽

Grand Challenge ◽

Pose Prediction ◽

Design Data ◽

Data Resource ◽

Affinity Ranking ◽

Ligand Similarity ◽

Bace 1

The Drug Design Data Resource (D3R) Grand Challenges present an opportunity to assess, in the context of a blind predictive challenge, the accuracy and the limits of tools and methodologies designed to help guide pharmaceutical drug discovery projects. Here, we report the results of our participation in the D3R Grand Challenge 4, which focused on predicting the binding poses and affinity ranking for compounds targeting the beta-amyloid precursor protein (BACE-1). Our ligand similarity-based protocol using HYBRID (OpenEye Scientific Software) successfully identified poses close to the native binding mode for most of the ligands with less than 2 A RMSD accuracy. Furthermore, we compared the performance of our HYBRID-based approach to that of AutoDock Vina and Dock 6 and found that HYBRID performed better here for pose prediction. We also conducted end-point free energy estimates on protein-ligand complexes using molecular mechanics combined with generalized Born surface area method (MM-GBSA). We found that the binding affinity ranking based on MM-GBSA scores have poor correlation with the experimental values. Finally, the main lessons from our participation in D3R Grand Challenge 4 suggest that: i) the generation of the macrocycles conformers is a key step for successful pose prediction, ii) the protonation states of the BACE-1 binding site should be treated carefully, iii) the MM-GBSA method could not discriminate well between different predicted binding poses, and iv) the MM-GBSA method does not perform well at predicting protein-ligand binding affinities here.

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Application of the ESMACS Binding Free Energy Protocol to a Highly Varied Ligand Dataset: Lactate Dehydogenase A

10.26434/chemrxiv.8398055 ◽

2019 ◽

Author(s):

David Wright ◽

Fouad Husseini ◽

Shunzhou Wan ◽

Christophe Meyer ◽

Herman Van Vlijmen ◽

...

Keyword(s):

Free Energy ◽

Surface Area ◽

Binding Free Energy ◽

Normal Mode Analysis ◽

Binding Mode ◽

Accessible Surface Area ◽

Solvent Accessible Surface Area ◽

Mode Analysis ◽

Energy Calculation ◽

Accessible Surface

<div>Here, we evaluate the performance of our range of ensemble simulation based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) for use in fragment based drug design scenarios. ESMACS is designed to generate reproducible binding affinity predictions from the widely used molecular mechanics Poisson-Boltzmann surface area (MMPBSA) approach. We study ligands designed to target two binding pockets in the lactate dehydogenase A target protein, which vary in size, charge and binding mode. When comparing to experimental results, we obtain excellent statistical rankings across this highly diverse set of ligands. In addition, we investigate three approaches to account for entropic contributions not captured by standard MMPBSA calculations: (1) normal mode analysis, (2) weighted solvent accessible surface area (WSAS) and (3) variational entropy. </div>

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Ruthenium(II) Complexes Bearing Thioether-Appended α- Iminopyridine Ligands: Arene Precursors Permit Access to K2-N,N and K3-N,N,S Complexes

10.26434/chemrxiv.9693506.v1 ◽

2019 ◽

Author(s):

Victoria A. Ternes ◽

Hannah A. Morgan ◽

Austin P. Lanquist ◽

Michael P. Murray ◽

Bradley Wile

Keyword(s):

Crystal Structure ◽

Solid State ◽

Strong Field ◽

Active Role ◽

Binding Mode ◽

Phenethyl Alcohol ◽

Ru Complexes

Herein we report the preparation of a series of Ru(II) complexes featuring alpha-iminopyridine ligands bearing thioether functionality (NNS<sup>R</sup>, where R = Me, CH<sub>2</sub>Ph, Ph). Metallation using (<i>p</i> cymene)RuCl dimer permits access to (k<sup>2</sup>-N,N)Ru complexes in which the thioether moiety remains uncoordinated. In the presence of a strong field ligand such as acetonitrile or triphenylphosphine, the p-cymene moiety is displaced, and the ligand adopts a k<sup>3</sup>-N,N,S binding mode. These complexes are characterized using a combination of solution and solid state methods, including the crystal structure of [(NNS<sup>Me</sup>)Ru(NCMe)<sub>2</sub>Cl]Cl. The k<sup>2</sup>-N,N Ru(II) complexes are shown to serve as efficient precatalysts for the oxidation of sec-phenethyl alcohol at 5 mol% loadings, using a variety of external oxidants and solvents. The complex bearing an S-Ph donor was found to be the most active of those surveyed, suggesting that the thioether donor plays an active role in catalyst speciation for this transformation.

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