Absolute Free Energy of Binding Calculations for Macrophage Migration Inhibitory Factor in Complex with a Druglike Inhibitor

Qian, Yue; Vilseck, Jonah Z.; Cole, D. J. A.; Tirado‐Rives, Julian; Jorgensen, William

doi:10.1021/acs.jpcb.9b07588

Cited by 26 publications

(33 citation statements)

References 56 publications

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“…Monte Carlo methods based on making unphysical, Boltzmann weighed rotamer and torsion moves lead to greater conformational sampling and crossing of energy barriers that would necessitate substantial simulation time in MD. Pure MC ( Cabeza de Vaca et al, 2018 ; Qian et al, 2019 ) and the hybrid MC/MD method Binding modes of Ligands Using Enhanced Sampling (BLUES) involving random ligand rotations, relaxation with MD, and final acceptance or rejection through nonequilibrium Monte Carlo are demonstrated to have greater binding mode sampling efficiency than standard MD. Hamiltonian replicas parallelize sampling backbone torsions of T4 lysozyme ( Jiang et al, 2018 ) and solvent exchange in the cytochrome P450 binding site ( Jiang, 2019 ) to speed convergence within 1 ns in the latter study.…”

Section: Free Energy Calculation Approachesmentioning

confidence: 99%

Recent Developments in Free Energy Calculations for Drug Discovery

King

Aitchison

et al. 2021

Front. Mol. Biosci.

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The grand challenge in structure-based drug design is achieving accurate prediction of binding free energies. Molecular dynamics (MD) simulations enable modeling of conformational changes critical to the binding process, leading to calculation of thermodynamic quantities involved in estimation of binding affinities. With recent advancements in computing capability and predictive accuracy, MD based virtual screening has progressed from the domain of theoretical attempts to real application in drug development. Approaches including the Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA), Linear Interaction Energy (LIE), and alchemical methods have been broadly applied to model molecular recognition for drug discovery and lead optimization. Here we review the varied methodology of these approaches, developments enhancing simulation efficiency and reliability, remaining challenges hindering predictive performance, and applications to problems in the fields of medicine and biochemistry.

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Section: Free Energy Calculation Approachesmentioning

confidence: 99%

Recent Developments in Free Energy Calculations for Drug Discovery

King

Aitchison

et al. 2021

Front. Mol. Biosci.

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“…蛋白质-配体结合自由能计算已经在药物设计、分子机器设计、超分子化学等领域得到了广泛的应用. 其中, Biggin 课题组证明采用基于约束的自由能计算方法, 在力场正确的条件下, 计算结果可以达到化学精度 (＜4.184 kJ/mol) [54] ; 罗海彬课题组通过将六自由度约束和 alchemistry 方法联用, 从候选小分子中筛选出了 15 种可能与新冠病毒主蛋白作用的药物 [55] ; Jorgensen 课题组通过计算蛋白质-配体的标准结合自由能, 比较了不同力场和电荷策略在描述蛋白质-配体化合物中的表现 [56] ; Chipot 课题组首次将计算蛋白质-配体准确结合自由能的思路拓展到蛋白质 -蛋白质领域 , 计算了 barnase-barstar 复合物的准确结合自由能 [57] ; Rizzi, Mobley 和 Chodera 课题组详尽地讨论了不同策略和软件实现在解决"SAMPL6 主客体结合预测挑战"上的表现 [58] . 本课题组采用基于七自由度约束和重要性采样策略, 研究了纺锤菌素和 DNA 的结合能力(图 5), 将准确结合自由能计算方法拓展到了任意主体-客体体系 [59] ; 探究了碗烯和苝在结合蛋白质能力上的差异, 阐明了具有立体结构的碗烯在和蛋白质作用上的优势 [60] .…”

Section: 蛋白质-配体准确结合自由能计算方法的应用unclassified

Accurate Estimation of Protein-ligand Binding Free Energies Based on Geometric Restraints

Fu¹,

Chen²,

Zhang³

et al. 2021

Acta Chimica Sinica

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Binding free energy is the most crucial physical quantity for describing recognition-association of protein-ligand hybrids. Accurate estimation of protein-ligand binding free energies is of paramount importance in the field of drug design and biological engineering. However, the association process of protein-ligand hybrids is usually coupled with complex conformational changes of molecular objects, which is not amenable to the timescale of classical molecular simulations. This limitation makes it difficult to accurately estimate the protein-ligand binding free energies using classical free-energy calculation strategies. An effective solution is to apply geometric restraints to reduce the configurational space needed to be sampled, so as to boost up the convergence rate of simulations, and then calculate and deduct the contribution of these restraints to the binding free energy by post-processing. In this review, we firstly introduce the recent developments of three geometric restraints, namely, funnel, spherical, and seven-degree-of-freedom restraints, used in accurate binding free-energy calculations, with emphasis on the latest progress of the third one. Specifically, the theoretically rigorous seven-degree-of-freedom restraint describes translational, orientational, rotational, and conformational degrees of freedom by means of a center-of-mass distance, spherical angles, Euler angles and the root-mean-square deviation. Moreover, we demonstrate the theoretical backgrounds and methods of how to achieve accurate protein-ligand binding free-energy estimation by combination of geometric restraints and importance-sampling or alchemical algorithms. In the geometric routes, the degrees of freedom of the relative movement of the protein-ligand complex are addressed in a stepwise fashion by one-dimensional importance-sampling simulations. In the alchemical routes, a special thermodynamics cycle is designed, in which additional simulations are performed to address the contribution of the restraints. A general suggestion for how to choose a suitable strategy for a given molecular assembly based on our experience is provided. Last but not least, we discuss the applications and challenges of using accurate protein-ligand binding free-energy calculation methods in fields such as drug design, and present the possibility of extending these methods for investigating complex protein-protein interaction.

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“…A number of named methods and approaches have been published for calculation of absolute binding free energies. [2][3][4][5][6][7][8][9][10][11][12] Named packages include BEDAM, 13 BFEE, 14,15 CHARMM-GUI, 16 XFEP, 17 and GA-FEP. 18 The performance of absolute binding free energy calculations depends on the protein and ligand forcefields used and, to date, there is a dearth of work on identifying the most effective protein and ligand forcefields.…”

Section: Introductionmentioning

confidence: 99%

Comparing the performance of different AMBER protein forcefields, partial charge assignments, and water models for absolute binding free energy calculations

Huggins

2022

Preprint

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Identifying chemical starting points is a vital first step in small molecule drug discovery and can take significant time and money. For this reason, computational approaches to virtual screening are of great interest as they can lower cost and shorten timeframes. However, simple approaches such as molecular docking and pharmacophore screening are of limited accuracy and provide a low probability of success. Alchemical binding free energies represent a promising approach for virtual screening as they naturally incorporate the key effects of water molecules, protein flexibility, and binding entropy. However, the calculations are technically very challenging, with performance depending on the specific forcefield used. For this reason, it is important that the community has access to benchmark test sets to assess prediction accuracy. In this paper we present an approach to alchemical binding free energies using OpenMM. We identify effective simulation parameters using an existing BRD4(1) test set and present two new benchmark sets (cMET and PDE2A) that can be used in the community for validation purposes. Our findings also highlight the effectiveness of some AMBER forcefields, in particular AMBER ff15ipq.

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Absolute Free Energy of Binding Calculations for Macrophage Migration Inhibitory Factor in Complex with a Druglike Inhibitor

Cited by 26 publications

References 56 publications

Recent Developments in Free Energy Calculations for Drug Discovery

Recent Developments in Free Energy Calculations for Drug Discovery

Accurate Estimation of Protein-ligand Binding Free Energies Based on Geometric Restraints

Comparing the performance of different AMBER protein forcefields, partial charge assignments, and water models for absolute binding free energy calculations

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