Accurate energy evaluation of receptor-ligand interaction
Lead Research Organisation:
University of Manchester
Department Name: Chemistry
Abstract
Drug design routinely uses existing computational methods to evaluate the interaction energy between receptor (protein) and ligand (drug) in molecular docking. The problem with these methods is that they are not reliable and accurate enough. One Perspective squarely asks "why docking remains so primitive that it is unable to even rank-order a hit list".
A more realistic and accurate force field will make the so-called scoring functions that docking uses more reliable. Our lab has a deep knowledge of a next-generation in-house force field called FFLUX.
This force field is much more realistic than a point-charge based force field such as AMBER. Moreover, FFLUX "sees the electrons" and is hence closer to the underlying quantum mechanics that ultimately governs the behaviour of all matter. FFLUX also introduces multipole moments, which is essential for accurate electrostatics.
There is a modern and accurate energy partitioning method called Interacting Quantum Atoms (IQA), which offers a step change in the rigour of atomistic energy analysis. IQA is a parameter-free method that is intuitive but, at the same time, very close to the quantum mechanical character of atoms themselves. Originally rooted in small molecules, our lab has demonstrated that IQA can be now feasibly used for systems up to ~350 atoms. However, we have shown in work to be published that smaller systems (~150 atoms) suffice to obtain rigorous insight.
Our in-house program ANANKE operates on a sequence of structures with varying distances and orientations of the receptor and ligand. ANANKE is able to highlight which fragments act like the total system, in terms of the various energetic contributions (both in type and locale). This is how, for the first time, a pharmacophore will be actually be computed.
We aim to make this emerging technology available to AstraZeneca and work on case studies relevant to the company. This is an innovative project that aims to enhance long overdue realism and accuracy in drug design.
A more realistic and accurate force field will make the so-called scoring functions that docking uses more reliable. Our lab has a deep knowledge of a next-generation in-house force field called FFLUX.
This force field is much more realistic than a point-charge based force field such as AMBER. Moreover, FFLUX "sees the electrons" and is hence closer to the underlying quantum mechanics that ultimately governs the behaviour of all matter. FFLUX also introduces multipole moments, which is essential for accurate electrostatics.
There is a modern and accurate energy partitioning method called Interacting Quantum Atoms (IQA), which offers a step change in the rigour of atomistic energy analysis. IQA is a parameter-free method that is intuitive but, at the same time, very close to the quantum mechanical character of atoms themselves. Originally rooted in small molecules, our lab has demonstrated that IQA can be now feasibly used for systems up to ~350 atoms. However, we have shown in work to be published that smaller systems (~150 atoms) suffice to obtain rigorous insight.
Our in-house program ANANKE operates on a sequence of structures with varying distances and orientations of the receptor and ligand. ANANKE is able to highlight which fragments act like the total system, in terms of the various energetic contributions (both in type and locale). This is how, for the first time, a pharmacophore will be actually be computed.
We aim to make this emerging technology available to AstraZeneca and work on case studies relevant to the company. This is an innovative project that aims to enhance long overdue realism and accuracy in drug design.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/N509565/1 | 01/10/2016 | 30/09/2021 | |||
| 1846924 | Studentship | EP/N509565/1 | 01/10/2017 | 06/07/2018 | Carlos Rubiera |