Evaluating the use of absolute binding free energy in the fragment optimisation process

Alibay, Irfan; Magarkar, Aniket; Seeliger, Daniel; Biggin, Philip C.

doi:10.1038/s42004-022-00721-4

Cited by 36 publications

(64 citation statements)

References 114 publications

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“…It is possible that the restraints between the phenol and this Asn, which quickly forms a H-bond to water upon its entry to the binding site, created particularly high barriers to the entry of water, giving rise to systematic error. Regardless, the difference observed suggests that the approach of running independent replicate simulations with different restraints, as taken by Alibay et al, is sensible.…”

Section: Resultsmentioning

confidence: 97%

“…For each pair, adjacent heavy atoms were selected to complete the sets of Boresch anchor points. These sets were ordered by increasing total variance of the Boresch DoF, as done by Alibay, , and sets of anchor points were discarded if the average values of θ A or θ B were below 30 or above 150 degrees. The equilibrium values for all restraints were taken to be their average values during the unrestrained simulation.…”

Section: Methodsmentioning

confidence: 99%

“…Algorithms have been proposed for the selection of Boresch restraints. ,,,− At a minimum, these aim to select stable restraints based on the geometry of the complex, while more sophisticated methods aim to enhance convergence by directly (e.g., based on H-bonds) or indirectly (based on minimum total variance of the distance, angles, and dihedrals) mimicking strong receptor–ligand interactions based on a short unrestrained simulation. However, there is no obviously superior method which has been shown to guarantee selection of numerically stable restraints with optimal convergence properties.…”

Section: Theorymentioning

confidence: 99%

See 2 more Smart Citations

Comparison of Receptor–Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations

Clark

Robb

Cole

et al. 2023

J. Chem. Theory Comput.

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Alchemical absolute binding free energy calculations are of increasing interest in drug discovery. These calculations require restraints between the receptor and ligand to restrict their relative positions and, optionally, orientations. Boresch restraints are commonly used, but they must be carefully selected in order to sufficiently restrain the ligand and to avoid inherent instabilities. Applying multiple distance restraints between anchor points in the receptor and ligand provides an alternative framework without inherent instabilities which may provide convergence benefits by more strongly restricting the relative movements of the receptor and ligand. However, there is no simple method to calculate the free energy of releasing these restraints due to the coupling of the internal and external degrees of freedom of the receptor and ligand. Here, a method to rigorously calculate free energies of binding with multiple distance restraints by imposing intramolecular restraints on the anchor points is proposed. Absolute binding free energies for the human macrophage migration inhibitory factor/MIF180, system obtained using a variety of Boresch restraints and rigorous and nonrigorous implementations of multiple distance restraints are compared. It is shown that several multiple distance restraint schemes produce estimates in good agreement with Boresch restraints. In contrast, calculations without orientational restraints produce erroneously favorable free energies of binding by up to approximately 4 kcal mol–1. These approaches offer new options for the deployment of alchemical absolute binding free energy calculations.

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Section: Resultsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Theorymentioning

confidence: 99%

See 1 more Smart Citation

Comparison of Receptor–Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations

Clark

Robb

Cole

et al. 2023

J. Chem. Theory Comput.

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show abstract

“…Finally, 853 simulation cases from 34 different research groups (from 47 papers, i.e. , refs , − ) and from distinct schools of thought ( i.e. , routes, force fields, etc .)…”

Section: Results and Discussionmentioning

confidence: 99%

Meta-Analysis Reveals That Absolute Binding Free-Energy Calculations Approach Chemical Accuracy

Zhou

Xiang

et al. 2022

J. Med. Chem.

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Systematic and quantitative analysis of the reliability of formally exact methods that in silico calculate absolute protein–ligand binding free energies remains lacking. Here, we provide, for the first time, evidence-based information on the reliability of these methods by statistically studying 853 cases from 34 different research groups through meta-analysis. The results show that formally exact methods approach chemical accuracy (error = 1.58 kcal/mol), even if people are challenging difficult tasks such as blind drug screening in recent years. The geometrical-pathway-based methods prove to possess a better convergence ability than the alchemical ones, while the latter have a larger application range. We also reveal the importance of always using the latest force fields to guarantee reliability and discuss the pros and cons of turning to an implicit solvent model in absolute binding free-energy calculations. Moreover, based on the meta-analysis, an evidence-based guideline for in silico binding free-energy calculations is provided.

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“…Since ligands are treated individually, they do not need to share a common scaffold and can be structurally diverse. This means that ABFE could be used even in early project stages where structurally diverse ligands are common and has been proposed to serve as a final scoring stage in virtual high throughput screening before selecting molecules for experimental testing. , Recent studies showed that ABFE can achieve a good correlation between predicted and experimental binding free energies across different systems − and can even be used to estimate binding to different proteins, allowing computation of the selectivity of ligands for a particular target …”

Section: Introductionmentioning

confidence: 99%

Broadening the Scope of Binding Free Energy Calculations Using a Separated Topologies Approach

Baumann

Dybeck

McClendon

et al. 2023

J. Chem. Theory Comput.

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Binding free energy calculations predict the potency of compounds to protein binding sites in a physically rigorous manner and see broad application in prioritizing the synthesis of novel drug candidates. Relative binding free energy (RBFE) calculations have emerged as an industry-standard approach to achieve highly accurate rank-order predictions of the potency of related compounds; however, this approach requires that the ligands share a common scaffold and a common binding mode, restricting the methods' domain of applicability. This is a critical limitation since complex modifications to the ligands, especially core hopping, are very common in drug design. Absolute binding free energy (ABFE) calculations are an alternate method that can be used for ligands that are not congeneric. However, ABFE suffers from a known problem of long convergence times due to the need to sample additional degrees of freedom within each system, such as sampling rearrangements necessary to open and close the binding site. Here, we report on an alternative method for RBFE, called Separated Topologies (SepTop), which overcomes the issues in both of the aforementioned methods by enabling large scaffold changes between ligands with a convergence time comparable to traditional RBFE. Instead of only mutating atoms that vary between two ligands, this approach performs two absolute free energy calculations at the same time in opposite directions, one for each ligand. Defining the two ligands independently allows the comparison of the binding of diverse ligands without the artificial constraints of identical poses or a suitable atom−atom mapping. This approach also avoids the need to sample the unbound state of the protein, making it more efficient than absolute binding free energy calculations. Here, we introduce an implementation of SepTop. We developed a general and efficient protocol for running SepTop, and we demonstrated the method on four diverse, pharmaceutically relevant systems. We report the performance of the method, as well as our practical insights into the strengths, weaknesses, and challenges of applying this method in an industrial drug design setting. We find that the accuracy of the approach is sufficiently high to rank order ligands with an accuracy comparable to traditional RBFE calculations while maintaining the additional flexibility of SepTop.

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Evaluating the use of absolute binding free energy in the fragment optimisation process

Cited by 36 publications

References 114 publications

Comparison of Receptor–Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations

Comparison of Receptor–Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations

Meta-Analysis Reveals That Absolute Binding Free-Energy Calculations Approach Chemical Accuracy

Broadening the Scope of Binding Free Energy Calculations Using a Separated Topologies Approach

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