A Branch‐and‐Bound Approach for Tautomer Enumeration

Thalheim, Torsten; Wagner, Barbara; Kühne, Ralph; Middendorf, Martin; Schüürmann, Gerrit

doi:10.1002/minf.201400128

Cited by 3 publications

(2 citation statements)

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“…Upon heating to 95 °C for elevated time periods, racemization (for amino acids with one stereogenic center) and epimerization (for amino acids with more than one center of chirality), respectively occur. It can be expected that a heat-induced movement of delocalized electrons within the electron clouds of the urea link leads to a reversible and short-term transient imine formation at the carbon atom of the chiral center (see abstract graphic) facilitated by keto–enol tautomerism , and charge-transfer effects . The planar imine structure induces the loss of chirality, hence providing an N -terminal stereo-interconversion of the attached amino acid.…”

Section: Resultsmentioning

confidence: 99%

Derivatize, Racemize, and Analyze—an Easy and Simple Procedure for Chiral Amino Acid Standard Preparation for Enantioselective Metabolomics

Horak

Lämmerhofer

2019

Anal. Chem.

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A simple, controllable, and reproducible stereoisomerization (racemization and epimerization) protocol for the preparation of scalemic α-amino acid mixtures from stereoisomerically pure standards was developed. Simply derivatize your amino acids with a racemization tag that incorporates a urea bond on the N-terminus of the target amino acid and incubate at elevated temperatures up to 95 °C for defined time periods until the targeted d-amino acid levels are obtained. The racemization tags investigated were 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC), aminophenyl-N-hydroxysuccinimidyl carbamate (AC), and 3-aminopyridyl-N-hydroxysuccinimidyl carbamate (APC). Employing this method, it was possible to create a ready-to-use, tailor-made chiral uniformly 13C and 15N labeled [U- 13C15N]-amino acid standard with the desired d-amino acid percentage within minutes or hours without sample cleanup. A racemization time of 30 min at 95 °C will lead to a d-amino acid level of 1–5%, while 6 h at 95 °C provides 15–30% d-amino acids. Racemization occurs due to imine formation at the chiral carbon atom bound to the urea-linking group without decomposition of labile amino acids such as Asn, Gln, Trp, Cit, and theanine. For amino acids possessing two chiral centers such as dl-Ile or dl-Thr, only the epimerization of isomers with different stereochemistry at the second chiral center will produce all four possible isobaric enantiomers. All measurements were performed on the zwitterionic Chiralpak ZWIX(+) column using a dual hydro-organic flow gradient combined with HPLC-ESI-QTOF-MS analysis. This new racemization method solves the problem of (enantioselective) matrix effects and inaccurate results in LC-MS based enantioselective metabolomics and warrants full MS-compatibility.

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Section: Resultsmentioning

confidence: 99%

Derivatize, Racemize, and Analyze—an Easy and Simple Procedure for Chiral Amino Acid Standard Preparation for Enantioselective Metabolomics

Horak

Lämmerhofer

2019

Anal. Chem.

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“…This is because it is a very complex combinatorial problem to solve. This software was published by Thalheim et al 78 in 2015, and uses a branch-and-bound (BnB) approach for tautomer enumeration. Their approach has the potential for fast and comprehensive tautomer generation, but imposes additional constraints on the tautomerism reactions which can be predicted.…”

Section: Introductionmentioning

confidence: 99%

Improving automated force-field parametrisation for molecular simulation: a graph approach

Caron¹

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Classical molecular dynamics (MD) techniques offer atomic-level insights into a wide range of physical systems, including biomolecular systems. They rely on empirical, parametrised equations (force fields) to describe the interaction potential between the constituents of the systems. Their predictive ability is critically dependent on the accuracy of these parameters. Highly optimised, well-validated parameters have been developed for many important biomolecules such as proteins, lipids and sugars. However, developing parameters for small molecules such as drugs is very challenging given the scale of chemical space. For instance, the ChEMBL database contains in excess of 1.7 million bioactive compounds. Although stand-alone software (e.g antechamber 1, 2 ) or web-servers (e.g. the Automated Topology Builder, 3-5 atb.uq.edu.au) have been developed to assign parameters to drug-like molecules, they usually rely on fitting to quantum-mechanical (QM) calculations in combination with sets of empirical rules, and their applicability is limited to small molecules (less than a few tens of atoms). Automated parametrisation of large, bio-active, and often biologically relevant molecules is still impractical and greatly limits the predictive power of simulations involving such compounds.This thesis focuses on the use of graph-based approaches to develop new automated parametrisation paradigms which can exploit large data sets to simultaneously develop and assign force field parameters.An efficient Linear Programming method for deducing the charge state and bond order, based only on the molecular connectivity and chemical elements of its atoms, was developed. The algorithm was validated against the MMFF94 dataset containing 761 molecules with manually assigned bond orders. The approach was extended to i) cap molecular fragments (molecules having some atoms with incomplete valences) and ii) enumerate tautomeric (protomerism) forms of molecules. These extensions can be used for solving various problems related to drug-design and fragment-based empirical force-field parametrisation and can be applied to molecules containing hundreds of atoms.A new method for predicting chemically equivalent atoms in a molecule was developed. This method relies on identifying automorphisms of the molecule. False positives (non-chemically equivalent atoms treated as equivalent by the previous approach) were addressed by implementing a series of exceptions for double bonds, non-invertable rings and stereotopic atoms, respectively. This method was used to symmetrise force-field terms between chemically equivalent atoms in the Automated Topology Builder (ATB, 3-5 atb.uq.edu.au).Building on these chemical equivalence relationships, a representation-independent, symmetrycorrected distance metric was developed (Blind RMSD). This facilitates the alignment of molecules with identical chemical graphs but different atom naming and indexing arbitrarily assigned. This approach was extended to fragments (i.e. subset of atoms in a molecules) for mapping graph n...

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