A5056535696- Computational Drug Discovery Methods
- Machine Learning in Materials Science
- Protein Structure and Dynamics
- Protein Degradation and Inhibitors
- Chemical Synthesis and Analysis
- Innovative Microfluidic and Catalytic Techniques Innovation
- Receptor Mechanisms and Signaling
- Enzyme Structure and Function
- Neuropeptides and Animal Physiology
- Process Optimization and Integration
- Advanced Chemical Physics Studies
- Biosimilars and Bioanalytical Methods
- Scientific Computing and Data Management
- Machine Learning and Data Classification
- Monoclonal and Polyclonal Antibodies Research
- Chemistry and Chemical Engineering
- Advanced biosensing and bioanalysis techniques
- Quantum Dots Synthesis And Properties
- Analytical Chemistry and Chromatography
- Molecular Junctions and Nanostructures
- Advanced Control Systems Optimization
- vaccines and immunoinformatics approaches
- Spectroscopy and Quantum Chemical Studies
- RNA and protein synthesis mechanisms
- Advanced Biosensing Techniques and Applications
Computational Physics (United States)
2025
Tissue Dynamics (Israel)
2025
Max Planck Institute for Multidisciplinary Sciences
2024-2025
Bayer (France)
2024
Max Planck Institute for Dynamics and Self-Organization
2024
University of Toronto
2021-2023
Vector Institute
2021-2023
Google (United States)
2023
Harvard University Press
2022
Massachusetts Institute of Technology
2021-2022
Free energy calculations based on molecular dynamics and thermodynamic cycles accurately reproduce experimental affinities of diverse bromodomain inhibitors.
ConspectusThe ongoing revolution of the natural sciences by advent machine learning and artificial intelligence sparked significant interest in material science community recent years. The intrinsically high dimensionality space realizable materials makes traditional approaches ineffective for large-scale explorations. Modern data tools developed increasingly complicated problems are an attractive alternative. An imminent climate catastrophe calls a clean energy transformation overhauling...
Using small, flat aromatic rings as components of fragments or molecules is a common practice in fragment‐based drug discovery and lead optimization. With an increasing focus on the exploration novel biological chemical space, their improved synthetic accessibility, 3D are attracting interest. This study presents detailed analysis 2D ring marketed drugs. Several measures properties were used, such type assemblies molecular shapes. The also took into account relationship between protein...
Relative ligand binding affinity calculations based on molecular dynamics (MD) simulations and non-physical (alchemical) thermodynamic cycles have shown great promise for structure-based drug design.
Binding selectivity is a requirement for the development of safe drug, and it critical property chemical probes used in preclinical target validation. Engineering adds considerable complexity to rational design new drugs, as involves optimization multiple binding affinities. Computationally, prediction challenge, generally applicable methodologies are still not available computational medicinal chemistry communities. Absolute free energy calculations based on alchemical pathways provide...
The accurate calculation of the binding free energy for arbitrary ligand-protein pairs is a considerable challenge in computer-aided drug discovery. Recently, it has been demonstrated that current state-of-the-art molecular dynamics (MD) based methods are capable making highly predictions. Conventional MD-based approaches rely on first principles statistical mechanics and assume equilibrium sampling phase space. In work we demonstrate absolute energies (ABFE) can also be obtained via...
Long-acting injectables are considered one of the most promising therapeutic strategies for treatment chronic diseases as they can afford improved efficacy, safety, and patient compliance. The use polymer materials in such a drug formulation strategy offer unparalleled diversity owing to ability synthesize with wide range properties. However, interplay between multiple parameters, including physicochemical properties polymer, make it very difficult intuitively predict performance these...
Designing functional molecules and advanced materials requires complex design choices: tuning continuous process parameters such as temperatures or flow rates, while simultaneously selecting catalysts solvents. To date, the development of data-driven experiment planning strategies for autonomous experimentation has largely focused on parameters, despite urge to devise efficient selection categorical variables. Here, we introduce Gryffin, a general-purpose optimization framework variables...
Synthetic polymers are versatile and widely used materials. Similar to small organic molecules, a large chemical space of such materials is hypothetically accessible. Computational property prediction virtual screening can accelerate polymer design by prioritizing candidates expected have favorable properties. However, in contrast often not well-defined single structures but an ensemble similar which poses unique challenges traditional representations machine learning approaches. Here, we...
PFI-3, a novel inhibitor targeting the bromodomains of essential components BAF/PBAF complex, affects differentiation ESC and TSC.
Binding free energy calculations that make use of alchemical pathways are becoming increasingly feasible thanks to advances in hardware and algorithms. Although relative binding (RBFE) starting find widespread use, absolute (ABFE) still being explored mainly academic settings due the high computational requirements uncertain predictive value. However, some drug design scenarios, RBFE not applicable ABFE could provide an alternative. Computationally cheaper end-point implicit solvent, such as...
Human transthyretin (TTR) is implicated in several fatal forms of amyloidosis. Many mutations TTR have been identified; most these are pathogenic, but some offer protective effects. The molecular basis underlying the vastly different fibrillation behaviours mutants poorly understood. Here, on neutron crystallography, native mass spectrometry and modelling studies, we propose a mechanism whereby can form amyloid fibrils via parallel equilibrium partially unfolded species that proceeds favour...
Our interpretation of ligand–protein interactions is often informed by high-resolution structures, which represent the cornerstone structure-based drug design. However, visual inspection and molecular mechanics approaches cannot explain full complexity interactions. Quantum Mechanics are too computationally expensive, but one method, Fragment Molecular Orbital (FMO), offers an excellent compromise has potential to reveal key that would otherwise be hard detect. To illustrate this, we have...
The design of proteins with novel ligand-binding functions holds great potential for application in biomedicine and biotechnology. However, our ability to engineer is still limited, current approaches rely primarily on experimentation. Computation could reduce the cost development process would allow rigorous testing understanding principles governing molecular recognition. While computational methods have proven successful early stages discovery process, optimization that can quantitatively...
Abstract Many applications of inorganic nanoparticles (NPs), including photocatalysis, photovoltaics, chemical and biochemical sensing, theranostics, are governed by NP optical properties. Exploration identification reaction conditions for the synthesis NPs with targeted spectroscopic characteristics is a time‐, labor‐, resource‐intensive task, as it involves optimization multiple interdependent conditions. Integration machine learning (ML) microfluidics (MF) offers accelerated synthesis....
Abstract Research challenges encountered across science, engineering, and economics can frequently be formulated as optimization tasks. In chemistry materials recent growth in laboratory digitization automation has sparked interest optimization-guided autonomous discovery closed-loop experimentation. Experiment planning strategies based on off-the-shelf algorithms employed fully research platforms to achieve desired experimentation goals with the minimum number of trials. However, experiment...
The recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods drug discovery. Accurately assessing absolute energies, although highly desired, remains a challenging endeavour, mostly limited to small model cases. Here, we demonstrate accurate first principles based estimates for 128 pharmaceutically relevant targets. We use novel rigorous method generate ensembles ligand its decoupled state. Not only do deliver affinity estimates,...
Optimization strategies driven by machine learning, such as Bayesian optimization, are being explored across experimental sciences an efficient alternative to traditional design of experiment. When combined with automated laboratory hardware and high-performance computing, these enable next-generation platforms for autonomous experimentation. However, the practical application approaches is hampered a lack flexible software algorithms tailored unique requirements chemical research. One...
Inhibition of inducible T-cell kinase (ITK), a nonreceptor tyrosine kinase, may represent novel treatment for allergic asthma. In our previous reports, we described the discovery sulfonylpyridine (SAP), benzothiazole (BZT), indazole (IND), and tetrahydroindazole (THI) series as ITK inhibitors how computational tools such dihedral scans docking were used to support this process. X-ray crystallography modeling applied provide essential insight into ITK-ligand interactions. However, "visual...
Conserved water molecules are of interest in drug design, as displacement such waters can lead to higher affinity ligands and some cases, contribute towards selectivity. Bromodomains, small protein domains involved the epigenetic regulation gene transcription, display a network four conserved their binding pockets have recently been focus intense medicinal chemistry efforts. Understanding why certain bromodomains displaceable others do not is extremely challenging, it remains unclear which...