New Paper on Optimization of Protein–Ligand Electrostatic Interactions

Alex Wade has just published his recent work on explicit solvent alchemical free-energy methods to maximize ligand binding affinity by optimizing partial. This methodology can be applied to known ligand–protein complexes to determine an optimized set of ligand partial atomic changes. Read it at the journal website.

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Alex Wade Publishes On Computational Fluorine Scanning

Alex has just published his second paper in the Journal of Chemical Information and Modeling entitled “Computational Fluorine Scanning Using Free-Energy Perturbation”. This method can be applied to molecular dynamics simulations of a single compound and make predictions for the best binders out of numerous fluorinated analogues. We tested the method on nine test systems: Renin, DPP4, Menin, P38, Factor Xa, CDK2, AKT, JAK2, and Androgen Receptor. The predictions were in excellent agreement with more rigorous alchemical free-energy calculations and in good agreement with experimental data for most of the test systems. However, the agreement with experiment was very poor in some of the test systems and this highlights the need for improved force fields in addition to accurate treatment of tautomeric and protonation states. The method is of particular interest due to the wide use of fluorine in medicinal chemistry to improve binding affinity and ADME properties. The promising results on this test case suggest that perturbative fluorine scanning will be a useful addition to the available arsenal of free-energy methods.

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A Large Scale Study of Hydration Environments Through Hydration Sites

New paper out in J Phys Chem B: “A Large Scale Study of Hydration Environments Through Hydration Sites”. Read it at the journal website.

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Congratulations to Dr Ben Irwin on receiving his doctorate

Congratulations to Dr Ben Irwin on receiving his doctorate. His thesis is entitled “Decompositions of Free Energies in Molecular Simulation”. Ben has joined Optibrium as a Senior Scientist.

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New Review in WIREs Computational Molecular Science

Check out our new publication in WIREs Computational Molecular Science called “Biomolecular simulations: From dynamics and mechanisms to computational assays of biological activity”. This is a broad review of biomolecular simulation written with members of the Collaborative Computational Project for Biomolecular Simulation (CCPBioSim).

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Paper in Proteins: Structure, Function and Bioinformatics

A new paper is out in Proteins: from work which was presented by Ben Irwin when he visited the Pasteur Institute late last year. The paper uses hydration sites to validate the most probable binding pose of two proteins from an ensemble of binding poses. The abstract of the paper is:
We have performed docking simulations on GABARAP …

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Alex Wade’s First Paper Published in J. Chem. Inf. Model.

Congratulations to Alex Wade for the just accepted manuscript in J. Chem. Inf. Model. entitled “Assimilating Radial Distribution Functions To Build Water Models with Improved Structural Properties”. The structural properties of three- and four-site water models are improved by extending the ForceBalance parametrization code to include a new methodology allowing for the targeting of any radial distribution function (RDF) during the parametrization of a force field. The mean squared difference (MSD) between the experimental and simulated RDFs contributes to an objective function, allowing for the systematic optimization of force field parameters to reach closer overall agreement with experiment. RDF fitting is applied to develop modified versions of the TIP3P and TIP4P/2005 water models in which the Lennard-Jones potential is replaced by a Buckingham potential. The optimized TIP3P-Buckingham and TIP4P-Buckingham potentials feature 93 and 98% lower MSDs in the OO RDF compared to the TIP3P and TIP4P/2005 models respectively, with marked decreases in the height of the first peak. Additionally, these Buckingham models predict the entropy of water more accurately, reducing the error in the entropy of TIP3P from 11 to 3% and the error in the entropy of TIP4P/2005 from 11 to 2%. These new Buckingham models have improved predictive power for many nonfitted properties particularly in the case of TIP3P. Our work directly demonstrates how the Buckingham potential can improve the description of water’s structural properties beyond the Lennard-Jones potential. Moreover, adding a Buckingham potential is a favorable alternative to adding interaction sites in terms of computational speed on modern GPU hardware.

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Presentation at the 2018 Workshop on Free Energy, Kinetics, & MSM in Drug Design

Dave spoke about our recent paper on “Estimating Atomic Contributions to Hydration and Binding using Free Energy Perturbation” at the recent 2018 Workshop on Free Energy, Kinetics, & MSM in Drug Design in Boston, MA. You can watch the presentation here.

 

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New paper in JCTC

Congratulations to Ben Irwin for the just accepted manuscript in JCTC. This paper entitled “Estimating Atomic Contributions to Hydration and Binding using Free Energy Perturbation” introduces formulae which when combined with a molecular dynamics free energy perturbation (FEP) simulation give an estimate of the contribution to a free energy change from each atom in the system. The formulae in the document are fully derived from the Zwanzig equation and the assumption that the system energy and free energy change can be split into contributions from each atom in the system. We apply the formulae to two systems, the calculation of the hydration free energy of a caffeine molecule and the calculation of the binding free energy of lopinavir to human immunodeficiency virus type-1 protease (HIV-1P). The results give a quantitative estimate which atoms in the respective molecules are strong contributors to the hydration/binding and which parts of the molecules are neutral or unfavourable. The paper has significant potential in the field of drug discovery as this method can be used as a tool to understand and improve the binding of ligands to targets. This method will also be of interest to any field of chemistry or physics which employs molecular dynamics simulations to measure free energy changes.

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Paper on Ligandability in Drug Discovery Today

We have recently published an article in Drug Discovery Today called “Quantitative metrics for drug target ligandability“. Ligandability is a prerequisite for druggability and is a much easier concept to understand, model and predict because it does not depend on the complex pharmacodynamic and pharmacokinetic mechanisms in the human body. In this review, we consider a metric for quantifying ligandability from experimental data. We discuss ligandability in terms of the balance between effort and reward. The metric is evaluated for a standard set of well-studied drug targets – some traditionally considered to be ligandable and some regarded as difficult. We suggest that this metric should be used to systematically improve computational predictions of ligandability, which can then be applied to novel drug targets to predict their tractability.

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Ben is visiting Dassault Systèmes/Biovia

Ben will travel to the Cambridge office to give a presentation titled “Using Inhomogeneous Fluid Solvation Theory to Measure Solvation Free Energy Changes”. He will present work from his PhD studies and wider work from the Huggins Lab. The presentation will also be cast to the Biovia office in San Diego.
The abstract of the talk …

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Lab Visit – Institut Pasteur, Paris

Ben is travelling to Paris to give a talk on 23rd November at the Institut Pasteur. The talk is titled “Predicting Protein-Protein Binding Using Surface Water Displacement: Application to the binding of GABARAP to the GABA(A) Receptor”, and discusses work in collaboration with P. L. Chau.

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Development of Allosteric Polo-like Kinase Inhibitor

Working with the Medical Research Council Cancer Unit, we have recently published a study charting the development of an inhibitor for the PLK1 polo-box domain. The paper titled “Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS” is published in Cell Chemical Biology

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Chemical Communications Article

We have just published a paper in Chemical Communications on “Computationally-Guided Optimization of Small-Molecule Inhibitors of the Aurora A Kinase – TPX2 Protein-Protein Interaction“. Working in collaboration with Dr Danny Cole at the University of Newcastle, we used free energy perturbation theory in combination with enhanced sampling to design two new small-molecule inhibitors of the Aurora A kinase – TPX2 protein-protein interaction.

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Bunsentagung 2017

Dave visited the the TU Kaiserslautern to attend the Bunsentagung 2017. On May 27th he presented a talk entitled “Calculation of Two-Particle Entropies in Bulk Fluids and Solutions”, based on our recent publication.

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New Paper In The Journal of Chemical Physics On Solvation Entropy

Congratulations to Ben Irwin on his publication in the Journal of Chemical Physics: “On the accuracy of one- and two-particle solvation entropies“. Evaluating solvation entropies directly and combining with direct energy calculations is one way of calculating free energies of solvation and is used by Inhomogeneous Fluid Solvation Theory (IFST). The configurational entropy of a fluid is a function of the interatomic correlations and can thus be expressed in terms of correlation functions. The entropies in this work are directly calculated from a truncated series of integrals over these correlation functions. Many studies truncate all terms higher than the solvent-solute correlations. This study includes an additional solvent-solvent correlation term and assesses the associated free energy when IFST is applied to a fixed Lennard-Jones particle solvated in neon. The strength of the central potential is varied to imitate larger solutes. Average free energy estimates with both levels of IFST are able to reproduce the estimate made using the Free energy Perturbation (FEP) to within 0.16 kcal/mol.

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Drug Discovery Seminar: Which data is required when and why?

Dave is attending a “Drug Discovery Seminar: Which data is required when and why?”,  jointly organised by the Cambridge Academy of Therapeutic Sciences and the Milner Therapeutics Institute. This training seminar, led by professional drug hunter Dr Olaf Ritzeler from Sanofi, will focus on the data requirements leading to and supporting the key milestones of target credentialing, lead selection and preclinical candidate nomination. Topic areas covered will include chemistry and pharmaceutics; pharmacodynamics and pharmacokinetics; safety and regulatory issues; and commercial concerns.

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MGMS Meeting on MD in Pharma

Dave is attending the MGMS meeting “MD in Pharma” at SOAS in London on the 11th of April 2017. The meeting is organised by Ben Cossins from UCB to provide a platform for industrial experts to talk about how their MD based approaches are making an impact in our respective industrial settings and comment on where this may lead us in the future.

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Scientific Computation in the University of Cambridge

Dave is attending “Scientific Computation Day” at the Cambridge Engineering Department as part of the Scientific Computation in the University of Cambridge initiative.

There will be a range of talks, covering the breadth of scientific computing which takes place in and around the University of Cambridge, as well as software engineering topics:

  • Engineering Computation launch
  • Scientific computing research around the University
  • Research Software Engineering and best practice in scientific software development, sustainability
  • Computing infrastructure and high-performance computing
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Lecture at the Institut de Chimie des Substances Naturelles

This week Dr Huggins will be visiting Dr Bogdan Iorga at the ICSN (Institut de Chimie des Substances Naturelles) in Paris. On Thursday 16th March he will be presenting a lecture at the institute entitled “Structure and Function of Water In Biomolecular Systems”.

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