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Publications & Presentations

Poster: Closing the loop between synthesis and design: Balancing optimisation of potency with selectivity

Wednesday, 25 October 2017 13:10
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Peter Hunt

This poster by Peter Hunt, Tamsin Mansley, Edmund Champness, Nicholas Foster & Matthew Segall was presented at the ACS Fall 2017 National Meeting & Exposition held in Washington DC, USA.


Drug discovery is a multi-parameter optimisation (MPO) process, in which the goal is to simultaneously optimise target potency, selectivity and a broad range of Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties, prioritising those compounds most likely to succeed against a project’s objectives. However, the ultimate goal is not simply to select from those compounds already available, but to design new compounds with an improved balance of properties.

De novo design approaches typically result in more in silico compound ideas than can reasonably be synthesised and tested. Assessment of these virtual compounds therefore requires development and use of in silico models which predict potency, or other properties, based upon information derived from the known structure-activity relationships (SAR). These predictive models can be used in an MPO assessment of selectivity, optimising for high potency at one receptor and low potency at others.

We present a truly MPO approach to de novo design, using Probabilistic Scoring and quantitative structure-activity relationship (QSAR) models to generate and prioritise high quality compounds ideas. This approach enables simultaneous optimisation of the virtual compounds for high potency with selectivity over multiple receptors, whilst also considering a balanced ADMET profile. It is exemplified with optimisation of selective dipeptidyl peptidase (DPP) inhibitors.


Improved quantum mechanical model of P450-mediated aromatic oxidation

Wednesday, 25 October 2017 13:17
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Rasmus Leth

Rasmus Leth gave this presentation at the ACS Fall 2017 National Meeting & Exposition held in Washington DC, USA.


The Cytochrome P450 enzymes (P450s) are a large family of monooxygenases involved in the metabolism of drugs via oxidative reactions such as C-H bond hydroxylation, epoxidation and heteroatom oxidation. It has become increasingly important, within drug development, to develop computer based methods to study and accurately predict P450-mediated metabolism of drugs. We recently published a method that uses quantum mechanical simulations to predict the regioselectivity and lability of cytochrome P450 metabolism [1]. This method uses AM1 calculations and Brønsted relationships to estimate the activation energies for the reaction mechanisms leading to P450 metabolism. This model provides accurate predictions of the regioselectivity of metabolism with faster calculation time than ab initio DFT calculations. However, we have continued to investigate opportunities to further improve the accuracy of the semi empirical methods for some oxidative mechanisms such as aromatic oxidation. In the present study, we model the transition state in the reaction coordinate prior to the intermediates formed during aromatic and aliphatic hydroxylation [1]. The ab initio DFT level of theory is used to model these reactions for a range of P450 3A4 substrates, for which experimental data on relative reaction rates are available.

Quantum mechanical models of P450-mediated aromatic oxidation

A transition state search is performed to calculate accurate activation energies that correlate well with the experimental data. Subsequently, semi-empirical QM methods are used in a similar transition state search to establish a relationship to these DFT based energies. A correlation between the energetics of DFT and semi-empirical QM methods has been established and this correlation has, in turn, been used to develop an improved predictive model for aromatic oxidation, that can provide a fast and increasingly accurate prediction for the P450 mediated metabolism of drugs.

(1) Tyzack, J.; Hunt, P.; Segall, M. J. Chem. Inf. Model. 2016, 56, 2180-2193.


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Re:All StarVue feedback welcome

Wednesday, 19 July 2017 01:36

Thanks for your kind words. Ocura strips the counter-ions from salts and only shows the neutral 'parent' compound to give a cleaner display. I'm sorry that this is not what you're looking for. Unfortunately, it's not possible to change this behaviour in the current version of Ocura. However, our full application StarDrop (www.optibrium.com/stardrop) provides much more control over the displayof...

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Re:All StarVue feedback welcome

Thursday, 13 July 2017 14:45

Thanks a lot for providing such a simple yet powerful program for chemists. truly helpful. just one question - has anyone noticed any problem with displaying structures of salts? I tried a test SDF file. the salt structure doesn't show, though it seems to look OK in another program. Thanks. Jim

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Streamlining Drug Discovery - Cambridge 18 May

Friday, 24 February 2017 02:18

Please join us at our free one-day symposium in collaboration with WuXi AppTec, Lhasa Ltd and BioSolveIT on 18 May 2017 Full details, including speakers, location and registration are available on the event website...

Category: Optibrium News & Announcements
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