A5041724634- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Machine Learning in Materials Science
- Various Chemistry Research Topics
- Mass Spectrometry Techniques and Applications
- Spectroscopy and Quantum Chemical Studies
- Advanced Chemical Physics Studies
- Chemical Synthesis and Analysis
- Molecular Junctions and Nanostructures
- RNA and protein synthesis mechanisms
- Enzyme Structure and Function
- Monoclonal and Polyclonal Antibodies Research
- Chemical Thermodynamics and Molecular Structure
- thermodynamics and calorimetric analyses
- Innovative Microfluidic and Catalytic Techniques Innovation
- Design Education and Practice
- Architecture and Computational Design
- Medical Imaging Techniques and Applications
- Impact of Light on Environment and Health
- Interactive and Immersive Displays
- Radiopharmaceutical Chemistry and Applications
- Spectroscopy and Chemometric Analyses
- Gene Regulatory Network Analysis
- Orthopedic Infections and Treatments
- Protein purification and stability
Janssen (Belgium)
2019-2025
TU Wien
2023
University of California, Irvine
2020-2021
ETH Zurich
2018-2021
Temple University
2021
University of Colorado Boulder
2021
University of Wisconsin–La Crosse
2014
Alchemical free energy calculations are a useful tool for predicting differences associated with the transfer of molecules from one environment to another. The hallmark these methods is use "bridging" potential functions representing \emph{alchemical} intermediate states that cannot exist as real chemical species. data collected bridging alchemical thermodynamic allows efficient computation energies (or in energies) orders magnitude less simulation time than simulating process directly....
We present a methodology for defining and optimizing general force field classical molecular simulations, we describe its use to derive the Open Force Field 1.0.0 small-molecule field, codenamed Parsley. Rather than using traditional atom typing, our approach is built on SMIRKS-native (SMIRNOFF) parameter assignment formalism, which handles increases in diversity specificity of definition without needlessly increasing complexity specification. Parameters are optimized with ForceBalance tool,...
We introduce the Open Force Field (OpenFF) 2.0.0 small molecule force field for drug-like molecules, code-named Sage, which builds upon our previous iteration, Parsley. OpenFF fields are based on direct chemical perception, generalizes easily to highly diverse sets of chemistries substructure queries. Like iterations, Sage generation was validated in protein–ligand simulations be compatible with AMBER biopolymer fields. In this work, we detail methodology used develop field, as well...
Drug discovery can be thought of as a search for needle in haystack: searching through large chemical space the most active compounds. Computational techniques narrow experimental follow up, but even they become unaffordable when evaluating numbers molecules. Therefore, machine learning (ML) strategies are being developed computationally cheaper complementary navigating and triaging libraries. Here, we explore how an protocol combined with first-principles based alchemical free energy...
Free energy calculations are rapidly becoming indispensable in structure-enabled drug discovery programs. As new methods, force fields, and implementations developed, assessing their expected accuracy on real-world systems (benchmarking) becomes critical to provide users with an assessment of the when these methods applied within domain applicability, developers a way assess impact methodologies. These assessments require construction benchmark-a set well-prepared, high quality corresponding...
Binding free energy calculations predict the potency of compounds to protein binding sites in a physically rigorous manner and see broad application prioritizing synthesis novel drug candidates. Relative (RBFE) have emerged as an industry-standard approach achieve highly accurate rank-order predictions related compounds; however, this requires that ligands share common scaffold mode, restricting methods' domain applicability. This is critical limitation since complex modifications ligands,...
In drug discovery, the in silico prediction of binding affinity is one major means to prioritize compounds for synthesis. Alchemical relative free energy (RBFE) calculations based on molecular dynamics (MD) simulations are nowadays a popular approach accurate ranking compounds. MD rely empirical force field parameters, which strongly influence accuracy predicted affinities. Here, we evaluate ability six different small-molecule fields predict experimental protein–ligand affinities RBFE set...
Abstract We here introduce the Aquamarine (AQM) dataset, an extensive quantum-mechanical (QM) dataset that contains structural and electronic information of 59,783 low-and high-energy conformers 1,653 molecules with a total number atoms ranging from 2 to 92 (mean: 50.9), containing up 54 28.2) non-hydrogen atoms. To gain insights into solvent effects as well collective dispersion interactions for drug-like molecules, we have performed QM calculations supplemented treatment many-body (MBD)...
Prioritizing molecules for synthesis is a key role of computational methods within medicinal chemistry. Multiple tools exist ranking molecules, from the cheap and popular molecular docking to more computationally expensive molecular-dynamics (MD)-based methods. It often questioned whether accuracy rigorous justifies higher cost associated calculation time. Here, we compared performance on binding small seven scoring functions five programs, one end-point method (MM/GBSA), two MD-based free...
Force fields are used in a wide variety of contexts for classical molecular simulation, including studies on protein-ligand binding, membrane permeation, and thermophysical property prediction. The quality these relies the force to represent systems.
We introduce the Open Force Field (OpenFF) 2.0.0 small molecule force field for drug-like molecules, code-named Sage, which builds upon our previous iteration, Parsley. OpenFF fields are based on direct chemical perception, generalizes easily to highly diverse sets of chemistries substructure queries. Like iterations, Sage generation was validated in protein-ligand simulations be compatible with AMBER biopolymer fields. In this paper we detail methodology used develop field, as well...
Alchemical free energy calculations are becoming an increasingly prevalent tool in drug discovery efforts. Over the past decade, significant progress has been made automating various aspects of this technique. However, one aspect hampering wider application is construction perturbation networks to connect ligands interest. More specifically, ligand pairs with large dissimilarities should be avoided since they can lower convergence and decrease accuracy. Here, we propose a technique for...
Alchemical free energy calculations using conventional molecular dynamics and thermodynamic integration rely on simulations performed at fixed values of the coupling parameter λ. When multiple conformers in equilibrium are separated by high barriers space orthogonal to λ, proper convergence may require extremely long simulations. Four main strategies can be employed address this orthogonal-sampling problem: (a) λ-variations, where λ change along circumvent barriers; (b) λ-extrapolations,...
Drug discovery is accelerated with computational methods such as alchemical simulations to estimate ligand affinities. In particular, relative binding free energy (RBFE) are beneficial for lead optimization. To use RBFE compare prospective ligands in silico, researchers first plan the simulation experiment, using graphs where nodes represent and graph edges transformations between ligands. Recent work demonstrated that optimizing statistical architecture of these perturbation improves...
Direct optimization against experimental condensed-phase properties concerning small organic molecules still represents the most reliable way to calibrate empirical parameters of a force field. However, compared corresponding calibration quantum-mechanical (QM) calculations isolated molecules, this approach is typically very tedious and time-consuming. The present article describes an integrated scheme for automated refinement force-field data, considering entire classes constructed using...
Free energy calculations are rapidly becoming indispensable in structure-enabled drug discovery programs. As new methods, force fields, and implementations developed, assessing their expected accuracy on real-world systems (benchmarking) becomes critical to provide users with an assessment of the when these methods applied within domain applicability, developers a way assess impact methodologies. These assessments require construction benchmark - set well-prepared, high quality corresponding...
Force fields form the basis for classical molecular simulations, and their accuracy is crucial quality of, instance, protein–ligand binding simulations in drug discovery. The huge diversity of small-molecule chemistry makes it a challenge to build parameterize suitable force field. Open Field Initiative combined industry academic consortium developing state-of-the-art In this report, members worked together objectively evaluate performance (referred here as OpenFF) produced by initiative on...
Alchemical free energy calculations are a useful tool for predicting differences associated with the transfer of molecules from one environment to another. The hallmark these methods is use "bridging" potential functions representing _alchemical_ intermediate states that cannot exist as real chemical species. data collected bridging alchemical thermodynamic allows efficient computation energies (or in energies) orders magnitude less simulation time than simulating process directly. While...
A new method is proposed to calculate alchemical free-energy differences based on molecular dynamics (MD) simulations, called the conveyor belt thermodynamic integration (CBTI) scheme. As in (TI), K replicas of system are simulated at different values coupling parameter λ. The number taken be even, and equally spaced a forward-turn-backward-turn path, akin (CB) between two physical end-states; as λ-dynamics (λD), λ-values associated with individual systems evolve time along simulation....
In drug discovery, the in-silico prediction of binding affinity is one major means to prioritize compounds for synthesis. Alchemical relative free energy (RBFE) calculations based on molecular dynamics (MD) simulations nowadays a popular approach accurate ranking compounds. MD rely empirical force field parameters, which strongly influence accuracy predicted affinities. Here, we evaluate ability six different small-molecule fields predict experimental protein-ligand affinities in RBFE set...
We introduce the Open Force Field (OpenFF)~2.0.0 small molecule force field for drug-like molecules, code-named Sage, which builds upon our previous iteration, Parsley. OpenFF fields are based on direct chemical perception, generalizes easily to highly diverse sets of chemistries substructure queries. Like iterations, Sage generation was validated in protein-ligand simulations be compatible with AMBER biopolymer fields. In this paper we detail methodology used develop field, as well...
Alchemical free energy methods have become indispensable in computational drug discovery for their ability to calculate highly accurate estimates of protein-ligand affinities. Expanded ensemble (EE) methods, which involve single simulations visiting all the alchemical intermediates, some key advantages calculation. However, there been relatively few examples published literature using expanded energies binding. In this paper, as a test we compute relative binding Open Force Field Initiative...
We here introduce the Aquamarine (AQM) dataset, an extensive quantum-mechanical (QM) dataset that contains structural and electronic information of 59,783 low-and high-energy conformers 1,653 molecules with a total number atoms ranging from 2 to 92 (mean:50.9), containing up 54 (mean:28.2) non-hydrogen atoms. To gain insights into solvent effects as well collective dispersion interactions for drug-like molecules, we have performed QM calculations supplemented treatment many-body (MBD)...