Perspective: Alchemical free energy calculations for drug discovery

Mobley, David L.; Klimovich, Pavel V.

doi:10.1063/1.4769292

Cited by 219 publications

(296 citation statements)

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“…[1][2][3] These calculations typically rely on the thermodynamic cycle in Figure 1, in which A is transformed alchemically (i.e., by directly changing simulation parameters) across a series of intermediate simulations into B both in the binding site ( G site ) and in solution ( G solv ). While these two transformations are alchemical and do not represent physically possible processes, their free energies can be used to compute the free energy of the physical process of interest: the difference between the binding free energies of A and B, or G • bind,A − G • bind,B .…”

Section: Introductionmentioning

confidence: 99%

“…In other words, the ligands are placed into the binding site in particular (known or guessed) orientations, and then if these orientations are not the global minimum orientations for either ligand, that ligand must reorient to obtain a converged result. 19 This reorientation will often be the slowest factor in obtaining a converged result for the free energy difference. If the ligands are orientationally restrained to each other (as a result of, for example, a single topology, but this also applies to the method of Michel et al 14 ), both alchemical endpoint simulations need to find their global minimum orientations, and the alchemical intermediate simulations must sample back and forth between both orientations, which may require the slow crossing of a significant energy barrier.…”

Section: Introductionmentioning

confidence: 99%

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Separated topologies—A method for relative binding free energy calculations using orientational restraints

Rocklin

Mobley

Dill

2013

The Journal of Chemical Physics

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Orientational restraints can improve the efficiency of alchemical free energy calculations, but they are not typically applied in relative binding calculations, which compute the affinity difference been two ligands. Here, we describe a new "separated topologies" method, which computes relative binding free energies using orientational restraints and which has several advantages over existing methods. While standard approaches maintain the initial and final ligand in a shared orientation, the separated topologies approach allows the initial and final ligands to have distinct orientations. This avoids a slowly converging reorientation step in the calculation. The separated topologies approach can also be applied to determine the relative free energies of multiple orientations of the same ligand. We illustrate the approach by calculating the relative binding free energies of two compounds to an engineered site in Cytochrome C Peroxidase.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Separated topologies—A method for relative binding free energy calculations using orientational restraints

Rocklin

Mobley

Dill

2013

The Journal of Chemical Physics

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“…However, the number of required binding free energy calculations scales linearly with the number of binding modes for this already computationally demanding approach, making it unappealing to consider multiple candidate binding modes separately in this manner. 1 This approach been exemplified recently in binding free energy studies on bromodomains; multiple binding modes were considered separately. The crys-tallographic binding mode was always found to have a higher affinity than other metastable binding modes.…”

Section: Ligand Binding Modes Are Important But Difficult To Predictmentioning

confidence: 99%

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

Gill¹,

Lim²,

Grinaway³

et al. 2018

Preprint

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Accurately predicting protein-ligand binding affinities and binding modes 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, fragmentlike 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. 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.

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“…B (6) where G r (Y c ,λ) is the free energy of the restrained system ( is a constant that makes the argument of the logarithm adimensional) and G(Y,λ) is the free energy of the unrestrained system at Y with respect to some immaterial reference state at Y * . In eqs 5 and 6, H(x,λ) is the Hamiltonian at the alchemical state λ with x encompassing all solvent, ligand, and receptor coordinates.…”

Section: ■ Introductionmentioning

confidence: 99%

Statistical Mechanics of Ligand–Receptor Noncovalent Association, Revisited: Binding Site and Standard State Volumes in Modern Alchemical Theories

Procacci

Chelli

2017

J. Chem. Theory Comput.

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The present paper is intended to be a comprehensive assessment and rationalization, from a statistical mechanics perspective, of existing alchemical theories for binding free energy calculations of ligand−receptor systems. In detail, the statistical mechanics foundation of noncovalent interactions in ligand−receptor systems is revisited, providing a unifying treatment that encompasses the most important variants in the alchemical approaches from the seminal double annihilation method [Jorgensen et al. J. Chem. Phys. 1988; 89, 3742] ■ INTRODUCTIONThe determination of the binding free energy in ligand− receptor systems is the cornerstone of drug discovery. In the last few decades, traditional molecular docking techniques in computer-assisted drug design have been modified, integrated, or superseded using methodologies relying on a more realistic description of the drug−receptor system. It has become increasingly clear that a microscopic description of the solvent is a crucial ingredient to reliably rank the affinity of putative ligands for a given target. 1,2 In the framework of atomistic molecular dynamics (MD) simulations with explicit solvent, several methods for rigorously determining the absolute binding free energy in noncovalently bonded systems have been devised. Most of these methodologies are based on the socalled alchemical route 3−5 (see refs 6−9 for recent reviews). In this approach, proposed for the first time by Jorgensen et al. 10,11 and named double annihilation method (DAM), the absolute binding free energy of the ligand−receptor system was obtained by setting up a thermodynamic cycle as indicated in Figure 1 in which the basic quantities to be estimated are the annihilation or decoupling free energies of the ligand in the bound state and in bulk water, indicated hereafter as ΔG b and ΔG u , respectively. These decoupling free energies correspond to the two closing branches of the cycle and are obtained by discretizing the alchemical path connecting the fully interacting and fully decoupled ligand in a number of intermediate nonphysical states and then running MD simulations for each of these states.Alchemical states are defined by a λ coupling parameter entering the Hamiltonian, varying between 1 and 0, such that at λ = 1 and λ = 0 one has the fully interacting and gas-phase ligand, respectively. ΔG b and ΔG u are usually recovered as a sum of the contributions from each of the λ windows by applying the free energy perturbation method 12 (FEP). Alternatively, and equivalently, one can compute the canonical average of the derivative of the Hamiltonian at the discrete λ points, obtaining the decoupling free energy via numerical thermodynamic integration (TI). 13 Finally, the thermodynamic cycle is closed by computing the difference between the two decoupling free energies along the alchemical path, ΔG b and ΔG u , obtaining the dissociation free energy in solution.Gilson et al. 14 criticized Jorgensen's theory 10 by pointing out that the resulting dissociation free energy does not de...

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Perspective: Alchemical free energy calculations for drug discovery

Abstract: Extremely precise free energy calculations of amino acid side chain analogs: Comparison of common molecular mechanics force fields for proteins The Journal of Chemical Physics 119, 5740 (2003)

Cited by 219 publications

References 141 publications

Separated topologies—A method for relative binding free energy calculations using orientational restraints

Separated topologies—A method for relative binding free energy calculations using orientational restraints

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

Statistical Mechanics of Ligand–Receptor Noncovalent Association, Revisited: Binding Site and Standard State Volumes in Modern Alchemical Theories

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