Duangkamol Gleeson

QM/MM As a Tool in Fragment Based Drug Discovery. A Cross-Docking, Rescoring Study of Kinase Inhibitors

The use of QM/MM based methods to optimize and rescore GOLD derived cross-docked protein-ligand poses has been investigated using a range of fragment-like kinase inhibitors where experimental data have been reported. Particular emphasis has been placed on rationalizing the potential benefits of the method in the increasingly popular fragment based drug discovery area. The results of this cross-docking, rescoring study on 9 protein ligand complexes suggest that the hybrid QM/MM calculations could prove useful in kinase fragment based drug discovery (FBDD). B3LYP/6-31G**//UFF derived enthalphies allow us to identify the correct X-ray pose from a range of plausible decoys 77% of the time, almost a doubling of the retrieval rate compared to GOLD (44%). In addition, this method provides us with a means to rapidly and accurately generate virtual protein-ligand complexes that will allow a program team to probe the existing interactions between the ligand and protein and search for additional interactions.

QM/MM Calculations in Drug Discovery: A Useful Method for Studying Binding Phenomena?

Herein we investigate whether QM/MM could prove useful as a tool to study the often subtle binding phenomena found within pharmaceutical drug discovery programs. The goal of this investigation is to determine whether it is possible to employ high level QM/MM calculations to answer specific questions around a binding event in a cycle time that is aligned with medicinal chemistry synthesis. To this end QM/MM calculations have been performed on four protein kinase-ligand complexes using five different levels of theory, using standard hardware, in an effort to assess their utility. We conclude that the accuracy and turnaround time of such calculations mean they could prove valuable to (1) probe the subtle nature of the interactions within protein active sites, (2) facilitate the interpretation of poorly resolved electron density, and (3) study the impact of substituent changes on the binding conformation or in the assessment of alternate scaffolds. In practice, the successful application of such methods will be limited by the size of the system under investigation, the level of theory used, and whether there is a need for conformational sampling.

A theoretical study of cis–trans isomerisation in H-ZSM5: probing the impact of cluster size and zeolite framework on energetics and structure

In this study the results from a series of calculations are reported that probe the influence of the QM cluster size and the extended framework treatment in ONIOM calculations. This is done by comparing the differences in the structures and energetics obtained during simulations of cis–trans isomerisation of butene in H-ZSM-5 at varying level of accuracy. Seven different models have been employed; 3T, 5T and 10T DFT cluster models, and to more effectively encode the extended framework of ZSM-5; 3T:46T, 5T:46T, 10T:46T DFT:MM ONIOM models, and a 46T DFT cluster model. The results show that irrespective of the exact QM cluster size, relatively small gasphase clusters show clear limitations due to the neglect of the extended framework. In particular, the structural and electronic implications of using the different zeolite models have been rigorously assessed using the multivariate statistical method principal components analysis (PCA).

Application of QM/MM and QM methods to investigate histone deacetylase 8

Computational chemistry plays an important supporting role in the early stages of drug discovery research. Such methods are not without flaws, however they can be very useful in the development and testing of hypothesises as well as prioritizing aspects of the exploration process. In this paper we discuss some common issues with employing hybrid quantum mechanical/molecular mechanical (QM/MM) methods in certain drug discovery applications. The QM/MM method provides a means to simulate large biological systems for moderate computational cost. We use the method to assess the metalloproteins, human deacetylases (HDACs), which are targets for a variety of medical conditions including neurodegenerative diseases and HIV infection. Metalloproteins in particular are a challenge to simulate using the rapid empirical methods preferred in the pharmaceutical industry. We report the use of a QM/MM scheme of only moderate computational cost to explore the active site as well as its catalytic reaction. We also demonstrate the value of the method over smaller QM clusters and show that the method is capable of describing the kinetic differences associated with replacing Zn2+ with other metal co-factors.

QM methods in structure based design: Utility in probing protein–ligand interactions

Small changes in ligand structure can lead to large unexpected changes in activity yet it is often not possible to rationalize these effects using empirical modeling techniques, suggesting more effective methods are required. In this study we investigate the use of high level QM methods to study the interactions found within protein-ligand complexes as improved understanding of these could help in the design of new, more active molecules. We study aspects of ligand binding in a set of protein ligand complexes containing ligand efficient, fragment-like inhibitors as these structures are often challenging to determine experimentally. To assess the reliability of our theoretical models we compare the MP2/6-31+G** QM results to the original X-ray coordinates and to QM/MM B3LYP/6-31G*//UFF results which we have previously reported. We also contrast these results with data obtained from an analysis of the distribution of comparable interactions found in (a) high resolution kinase complexes (≤ 1.8Å) from the PDB and (b) more generic, small molecule crystal structures from the CSD.

Correction: Application of QM/MM and QM methods to investigate histone deacetylase 8

Correction for ‘Application of QM/MM and QM methods to investigate histone deacetylase 8’ by Duangkamol Gleeson et al., Med. Chem. Commun., 2015, 6, 477–485.