End-Point Affinity Estimation of Galectin Ligands by Classical and Semiempirical Quantum Mechanical Potentials

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 4, 2025

The use of quantum mechanical potentials in protein–ligand affinity prediction is becoming increasingly feasible with growing computational power. To move forward, validation such on real-world challenges necessary. this end, we have collated an extensive set over a thousand galectin inhibitors known affinities and docked them into galectin-3. poses were then used to systematically evaluate several modern force fields semiempirical (SQM) methods up the tight-binding level under consistent workflow. Implicit solvation models available tested simulate effects. Overall, best study achieved Pearson correlation 0.7–0.8 between computed experimental affinities. There differences their ability rank ligands across entire ligand as well within subsets structurally similar ligands. A major discrepancy was observed for subset that bind protein via halogen bond, which clearly challenging all methods. inclusion entropic term calculated by rigid-rotor-harmonic-oscillator approximation at SQM slightly worsened experiment but brought closer values. We also found success strongly depended model. Furthermore, provide in-depth analysis individual energy terms effect overall accuracy.

Language: Английский

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Understanding the impact of binding free energy and kinetics calculations in modern drug discovery

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: 19(6), P. 671 - 682

Published: May 9, 2024

Introduction For rational drug design, it is crucial to understand the receptor-drug binding processes and mechanisms. A new era for use of computer simulations in predicting drug-receptor interactions at an atomic level has begun with remarkable advances supercomputing methodological breakthroughs.

Language: Английский

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Software Infrastructure for Next-Generation QM/MM−ΔMLP Force Fields

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(26), P. 6257 - 6271

Published: June 21, 2024

We present software infrastructure for the design and testing of new quantum mechanical/molecular mechanical machine-learning potential (QM/MM-ΔMLP) force fields a wide range applications. The integrates Amber's molecular dynamics simulation capabilities with fast, approximate models in xtb package corrections DeePMD-kit. implements recently developed density-functional tight-binding QM multipolar electrostatics density-dependent dispersion (GFN2-xTB), interface Amber enables their use periodic boundary QM/MM simulations linear-scaling particle-mesh Ewald electrostatics. accuracy semiempirical is enhanced by including correction potentials (ΔMLPs) enabled through an DeePMD-kit software. goal this paper to validate implementation free energy simulations. utility demonstrated proof-of-concept example elements presented here are open source freely available. Their provides powerful enabling technology QM/MM-ΔMLP studying problems, biomolecular reactivity protein-ligand binding.

Language: Английский

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Alchemical Transformations and Beyond: Recent Advances and Real-World Applications of Free Energy Calculations in Drug Discovery

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(19), P. 7214 - 7237

Published: Oct. 3, 2024

Computational methods constitute efficient strategies for screening and optimizing potential drug molecules. A critical factor in this process is the binding affinity between candidate molecules targets, quantified as free energy. Among various estimation methods, alchemical transformation stand out their theoretical rigor. Despite challenges force field accuracy sampling efficiency, advancements algorithms, software, hardware have increased application of energy perturbation (FEP) calculations pharmaceutical industry. Here, we review practical applications FEP discovery projects since 2018, covering both ligand-centric residue-centric transformations. We show that relative steadily achieved chemical real-world applications. In addition, discuss alternative physics-based simulation incorporation deep learning into calculations.

Language: Английский

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Alchemical Enhanced Sampling with Optimized Phase Space Overlap

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: 20(9), P. 3935 - 3953

Published: April 26, 2024

An alchemical enhanced sampling (ACES) method has recently been introduced to facilitate importance in free energy simulations. The achieves from Hamiltonian replica exchange within a dual topology framework while utilizing new smoothstep softcore potentials. A common problem encountered lead optimization is the functionalization of aromatic rings that exhibit distinct conformational preferences when interacting with protein. It difficult converge distribution ring conformations due long time scale flipping events; however, ACES addresses this issue by modeling syn and anti topology. thereby samples conformer distributions alchemically tunneling between states, as opposed traversing physical pathway high rotational barrier. We demonstrate use overcome issues involving ML300-derived noncovalent inhibitors SARS-CoV-2 Main Protease (Mpro). demonstrations explore how choice selection affects convergence conformation distributions. Furthermore, we examine accuracy calculated energies affected degree phase space overlap (PSO) adjacent states (i.e., neighboring λ-windows) acceptance ratios. Both these factors are sensitive spacing intermediate states. introduce for choosing schedule λ values. analyzes short "burn-in" simulations construct 2D map nonlocal PSO. obtained optimizing an on equalizes PSO intervals. optimized λ-spacing (Opt-PSO) leads more numerous end-to-end single passes round trips correlation improved statistics enhance efficiency method. implemented into FE-ToolKit software package, which freely available.

Language: Английский

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Convergence-Adaptive Roundtrip Method Enables Rapid and Accurate FEP Calculations

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 5, 2024

The free energy perturbation (FEP) method is a powerful technique for accurate binding calculations, which crucial identifying potent ligands with high affinity in drug discovery. However, the widespread application of FEP limited by computational cost required to achieve equilibrium sampling and challenges obtaining converged predictions. In this study, we present convergence-adaptive roundtrip (CAR) method, an enhanced adaptive approach, address key including precision-efficiency tradeoff, efficiency, convergence assessment. By employing on-the-fly analysis automatically adjust simulation times, enabling efficient traversal important phase space through rapid propagation conformations between different states eliminating need multiple parallel simulations, CAR increases minimizes overhead while maintaining calculation accuracy. performance was evaluated relative (RBFE) calculations on benchmarks comprising four diverse protein-ligand systems. results demonstrated significant speedup over 8-fold compared conventional methods overall

Language: Английский

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Automated Adaptive Absolute Binding Free Energy Calculations

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 10, 2024

Alchemical absolute binding free energy (ABFE) calculations have substantial potential in drug discovery, but are often prohibitively computationally expensive. To unlock their potential, efficient automated ABFE workflows required to reduce both computational cost and human intervention. We present a fully workflow based on the selection of λ windows, ensemble-based detection equilibration, adaptive allocation sampling time inter-replicate statistics. find that intermediate states with consistent overlap is rapid, robust, simple implement. Robust equilibration achieved paired

Language: Английский

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Multiple Topology Replica Exchange of Expanded Ensembles for Multidimensional Alchemical Calculations

Journal of Chemical Theory and Computation, Journal Year: 2025, Volume and Issue: 21(1), P. 230 - 240

Published: Jan. 2, 2025

Relative free energy (RFE) calculations are now widely used in academia and the industry, but their accuracy is often limited by poor sampling of complexes' conformational ensemble. To help address problems when simulating many relative binding energies, we developed a novel method termed multiple topology replica exchange expanded ensembles (MT-REXEE). This enables parallel ensemble calculations, facilitating iterative RFE computations while allowing between transformations. These transformations can be adaptable to any set systems with common backbone or central substructure. We demonstrate that MT-REXEE maintains thermodynamic cycle closure same extent as standard for both solvation calculations. The tested involve incorporate diverse heavy atoms multisite perturbations small molecule core resembling λ dynamics, without necessitating modifications MD code. Our initial implementation GROMACS. outline systematic approach setup provide instructions on how perform inter-replica coordinate modifications. work shows accurate reproducible estimates prompts expansion more complex test other molecular dynamics simulation infrastructures.

Language: Английский

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A partition function estimator

The Journal of Chemical Physics, Journal Year: 2025, Volume and Issue: 162(2)

Published: Jan. 8, 2025

We propose an estimator that allows us to calculate the value of a simple system’s partition function using finite sampling. The core idea is neglect contribution from high energy microstates, which are difficult be sampled properly, and then volume correction term compensate for this. As proof concept, applied several model systems, ranging harmonic oscillator Lennard-Jones fluid with hundreds particles. Our results agree well numerically exact solutions or reference data, demonstrating efficiently estimating functions studied example cases possible computationally affordable.

Language: Английский

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Ligand and Residue Free Energy Perturbations Solve the Dual Binding Mode Proposal for an A_2BAR Partial Agonist

The Journal of Physical Chemistry B, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Adenosine receptors, particularly A2BAR, are gaining attention for their role in pathological conditions such as cancer immunotherapy, prompting the exploration promising therapeutic applications. Despite numerous selective A2BAR antagonists, lack of full agonists makes partial agonist BAY60-6583 one most interesting activators this receptor. Recent cryo-EM structures have univocally revealed binding mode nonselective ribosidic adenosine and its derivative NECA to A2BAR; however, two independent with show alternative orientations, raising question which is physiologically relevant mode. In situations this, computational simulations that accurately predict shifts free energy can complement experimental structures. Our study combines QligFEP QresFEP protocols directly compare affinity between modes well providing a direct comparison silico mutagenesis studies on each pose mutational effects. Both methods converge experimentally determined better explains both existing SAR data ligand. results allow elucidation orientation should be considered basis designing derivatives improved selectivity underscore value perturbation aiding structure-based drug design.

Language: Английский

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