Neeb M.,University of Marburg |
Czodrowski P.,Computational Chemistry |
Heine A.,University of Marburg |
Barandun L.J.,ETH Zurich |
And 3 more authors.
Journal of Medicinal Chemistry | Year: 2014
Drug molecules should remain uncharged while traveling through the body and crossing membranes and should only adopt charged state upon protein binding, particularly if charge-assisted interactions can be established in deeply buried binding pockets. Such strategy requires careful pKa design and methods to elucidate whether and where protonation-state changes occur. We investigated the protonation inventory in a series of lin-benzoguanines binding to tRNA-guanine transglycosylase, showing pronounced buffer dependency during ITC measurements. Chemical modifications of the parent scaffold along with ITC measurements, pKa calculations, and site-directed mutagenesis allow elucidating the protonation site. The parent scaffold exhibits two guanidine-type portions, both likely candidates for proton uptake. Even mutually compensating effects resulting from proton release of the protein and simultaneous uptake by the ligand can be excluded. Two adjacent aspartates induce a strong pKa shift at the ligand site, resulting in protonation-state transition. Furthermore, an array of two parallel H-bonds avoiding secondary repulsive effects contributes to the high-affinity binding of the lin-benzoguanines. © 2014 American Chemical Society.
Brown M.F.,Worldwide Medicinal Chemistry |
Mitton-Fry M.J.,Worldwide Medicinal Chemistry |
Arcari J.T.,Worldwide Medicinal Chemistry |
Barham R.,Worldwide Medicinal Chemistry |
And 28 more authors.
Journal of Medicinal Chemistry | Year: 2013
Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1. © 2013 American Chemical Society.
The process can help convert solar energy into usable electricity, or drive molecular machines whose parts rotate when an infusion of light prompts the molecules to change shape. To propel these and other technologies forward, a University at Buffalo researcher has developed a new tool for studying photoexcitation: a computer program called Libra. The open-source software gives scientists the building blocks to design their own algorithms for studying how a material or electronic state evolves over time. Among the program's capabilities: simulating what happens over time when a specific material is exposed to light. Photoexcitation can alter molecules in ways that are invisible to microscopes, but important to understand. These changes, which can sometimes cause molecules to behave differently or adjust their shape, can be modeled using algorithms designed through Libra. "Libra gives researchers a way to study the properties of many novel materials without having to fabricate each one experimentally," said the program's developer, Alexey Akimov, an assistant professor of chemistry in the UB College of Arts and Sciences. "This helps save time and money, as it takes resources to synthesize new materials in the lab." So if a scientist is trying to build a molecular machine with a propeller that moves in a certain direction when exposed to light, he or she could use Libra to identify the molecular structures most likely to perform this task efficiently before deciding which structures to actually create in experiments. Libra's capabilities are described in an article published on March 26, in the Journal of Computational Chemistry. Explore further: Tiny, light-activated crystal sponges fail over time. Why? More information: Alexey V. Akimov. Libra: An open-Source "methodology discovery" library for quantum and classical dynamics simulations, Journal of Computational Chemistry (2016). DOI: 10.1002/jcc.24367
These findings were revealed in the 6th blind test of crystal structure prediction, an exercise conducted by twenty five international research groups that was organised by the Cambridge Crystallographic Data Centre (CCDC). Crystal structures describe the periodically repeating arrangement of molecules in a material and determine many of a material's properties, such as solubility, dissolution rate, hardness, colour and external shape. The ability to predict crystal structures could therefore enable the design of materials with superior properties, for example the creation of brighter pigments, more effective pharmaceuticals, or even lower calorie foodstuff. In particular, the pharmaceutical industry would gain huge benefit from being able to reliably predict crystal structure because pharmaceutical molecules are prone to crystallise in more than one crystal structure (or polymorph), depending on the conditions under which the molecule is crystallised. The specific polymorph that goes into a formulation must be strictly controlled to ensure consistency of delivery to the patient. The ability to predict crystal structures could save pharmaceutical companies time and money by being able to quickly identify and develop polymorphs with superior properties. It would also help pharmaceutical companies with patent protection and product life cycle management. Different approaches to the problem have been developed and these have been evaluated over the years in international exercises, known as the blind tests of crystal structure prediction. Twenty five research groups who have been developing methods for predicting crystal structures of organic molecules took part in the latest test. In this test participants were challenged to predict nine recently determined crystal structures of five target compounds given only the chemical diagram of the molecules and conditions of crystallisation, with two sets of predictions allowed per target compound. Only one group managed to predict nearly all targets correctly. These very successful results were obtained by Dr Marcus Neumann of Avant-garde Materials Simulation and Prof Frank Leusen and Dr John Kendrick of the University of Bradford. Dr Marcus Neumann, author of the computer program GRACE for crystal structure prediction, which predicted eight out of nine targets correctly in this blind test and eight out of ten targets in the previous two blind tests, said: "Obviously, we are delighted with these results, in particular because unlike in earlier blind tests they have been obtained by a fully automated procedure that can be used as a black box in industrial working environments." Dr Frank Leusen, Professor of Computational Chemistry, University of Bradford, said: "I am particularly impressed that GRACE correctly predicted the crystal structure of a hydrated chloride salt, which poses a real challenge both in terms of the size of the search problem and in terms of the required accuracy. This result will be of particular interest to the pharmaceutical industry as they often deal with this type of compound." Dr John Kendrick, University of Bradford, added: "Recent developments within the Grace package meant that the process of predicting the crystal structures in the Blind Test was nearly automatic, very little intervention was required from the user." Although the whole problem is not solved - the predictions cannot yet explain the influence of solvent, impurities, additives or temperature on the outcome of a crystallisation experiment - these recent results demonstrate significant capabilities in the field. The results of previous blind tests, in 1999, 2001, 2004, 2007 and 2010, demonstrated that the crystal structures of small organic molecules can be predicted under favourable conditions. Success rates were low in the first three blind tests, but the fourth blind test in 2007 saw a major breakthrough with one group predicting all four target crystal structures, each as their most likely prediction. This was achieved by the same group of Drs. Neumann, Kendrick and Leusen who collaborated to predict eight out of nine targets in the latest blind test. The target compounds in the fifth blind test in 2010 became significantly more complex, but the success rate remained high, with particularly good results for a large flexible molecule which could be regarded as a prototype pharmaceutical compound. In the current, sixth, blind test, there were five targets, including a small semi-rigid molecule, a medium sized flexible molecule with five known polymorphs, a hydrated Chloride salt, a co-crystal and a large flexible molecule. The results were discussed at the Blind Test workshop on 27 and 28 October 2015 at the Cambridge Crystallographic Data Centre and featured in the journal Nature. Explore further: Tough crystal nut cracked: Correct prediction of all three known crystal structures of a sulfonimide
« Convergent Science forms Computational Chemistry Consortium | Main | GM recycles water bottles to make part for Chevy Equinox, coat insulation for the homeless, air filters » The 2016 SAE World Congress is again featuring a technical track (PFL 720) on advances in hydrogen fuel cell vehicle technology, followed by a technical expert panel discussion (PFL 799) on the commercialization of fuel cell vehicles and hydrogen infrastructure. The PFL 720 / 799 sessions are on Thursday, 14 April, in room 420A, Cobo Hall. During the PFL 720 sessions at last year’s Congress, Toyota presented a set of four technical papers describing some of the technology innovations used in its production fuel cell hybrid electric vehicle Mirai. (Earlier post.) As was the case last year, the 2016 PFL 720 / PFL 799 combination is chaired by Jesse Schneider of BMW. The PFL 799 panel, an annual wrap-up after the technical sessions, this year features: