Tailored Polymer-Supported Templates in Dynamic Combinatorial Libraries: Simultaneous Selection, Amplification and Isolation of Synthetic Receptors

2008 ◽  
Vol 14 (29) ◽  
pp. 9006-9019 ◽  
Author(s):  
Pol Besenius ◽  
Peter A. G. Cormack ◽  
Jingyuan Liu ◽  
Sijbren Otto ◽  
Jeremy K. M. Sanders ◽  
...  
Keyword(s):  
Combinatorial Libraries ◽  
Synthetic Receptors ◽  
Polymer Supported ◽  
Simultaneous Selection

Characterization of Soluble Polymer Supported Organic Molecules by Mass Spectrometry

2003 ◽  
Vol 804 ◽  
Author(s):  
C. Enjalbal ◽  
F. Lamaty ◽  
P. Ribière ◽  
S. Varray ◽  
E. Suberchicot ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Organic Molecules ◽  
Solid Phase ◽  
Combinatorial Libraries ◽  
Maldi Mass Spectrometry ◽  
Soluble Polymer ◽  
Polymer Solubility ◽  
Esi Mass Spectrometry ◽  
Polymer Supported ◽  
Phase Chemistry

ABSTRACTSyntheses carried out on soluble polymers, such as polyethylene glycol (PEG), benefit the advantages of both solution-phase and solid-phase syntheses. The choice of the reaction solvent governs the polymer solubility. Synthetic steps are conducted under homogeneous conditions whereas purifications are performed by filtration after polymer precipitation. This alternative strategy, known as liquid-phase chemistry, has been investigated to prepare combinatorial libraries.The fact that soluble polymer supported molecules are directly amenable to standard spectroscopic methods, including NMR (1H, 13C) and ESI or MALDI mass spectrometry (ElectroSpray and Matrix Assisted Laser Desorption Ionization) allows to perform to in situ reaction monitoring without the need to release the compound from the polymeric support.We report a general methodology to characterize step by step soluble polymer supported organic molecules by MALDI and ESI mass spectrometry. High throughput analyses were targeted to fullfil combinatorial chemistry requirements. Data acquisition and interpretation were automated through the design of specific experimental protocols and a data managment software. MALDI mass spectrometry was appropriate to analyze pure supported molecules whereas ESI mass spectrometry coupled to liquid chromatography was required to unravel PEG mixtures.

Automated, Accurate, and Scalable Relative Protein-Ligand Binding Free Energy Calculations using Lambda Dynamics

2020 ◽  
Author(s):  
E. Prabhu Raman ◽  
Thomas J. Paul ◽  
Ryan L. Hayes ◽  
Charles L. Brooks III
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Computational Cost ◽  
Combinatorial Libraries ◽  
Free Energy Calculations ◽  
Lead Optimization ◽  
Efficient Estimation ◽  
Lead Compound

<p>Accurate predictions of changes to protein-ligand binding affinity in response to chemical modifications are of utility in small molecule lead optimization. Relative free energy perturbation (FEP) approaches are one of the most widely utilized for this goal, but involve significant computational cost, thus limiting their application to small sets of compounds. Lambda dynamics, also rigorously based on the principles of statistical mechanics, provides a more efficient alternative. In this paper, we describe the development of a workflow to setup, execute, and analyze Multi-Site Lambda Dynamics (MSLD) calculations run on GPUs with CHARMm implemented in BIOVIA Discovery Studio and Pipeline Pilot. The workflow establishes a framework for setting up simulation systems for exploratory screening of modifications to a lead compound, enabling the calculation of relative binding affinities of combinatorial libraries. To validate the workflow, a diverse dataset of congeneric ligands for seven proteins with experimental binding affinity data is examined. A protocol to automatically tailor fit biasing potentials iteratively to flatten the free energy landscape of any MSLD system is developed that enhances sampling and allows for efficient estimation of free energy differences. The protocol is first validated on a large number of ligand subsets that model diverse substituents, which shows accurate and reliable performance. The scalability of the workflow is also tested to screen more than a hundred ligands modeled in a single system, which also resulted in accurate predictions. With a cumulative sampling time of 150ns or less, the method results in average unsigned errors of under 1 kcal/mol in most cases for both small and large combinatorial libraries. For the multi-site systems examined, the method is estimated to be more than an order of magnitude more efficient than contemporary FEP applications. The results thus demonstrate the utility of the presented MSLD workflow to efficiently screen combinatorial libraries and explore chemical space around a lead compound, and thus are of utility in lead optimization.</p>

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