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Computationally guided design of N4-(2-methyl-2H-indazol-6-yl)-N2-phenylpyrimidine-2,4-diamine inhibitors of EGFR kinase targeting Cys797
(2026-03-01)
Konsue, Adchata
;
Gleeson, Duangkamol
;
Choowongkomon, Kiattawee
;
Jones, Donald J.L.
;
Hannanta-anan, Pimkhuan
The epidermal growth factor receptor kinase (EGFR) is a tyrosine kinase (TK) implicated in the uncontrolled growth of non-small cell lung cancer. EGFR-TK inhibitors have been used extensively, however inhibitor resistance often develops leading to disease progression. In this work, we report the computationally guided design and preparation of novel covalent 2,4-diaminopyrimidine EGFR-TK inhibitors, inspired by Osimertinib. Molecular dynamics simulations and quantum mechanical (QM) calculations were performed on novel designs incorporating a 2-methyl-2H-indazol-6-amine at the 4-position of pyrimidine as well as various linkers and electrophiles. Calculations suggested swapping the 5-pyrimidine -H atom for -Cl would lead to a preferential “out” ligand conformation that favored T790M enzyme which was later confirmed experimentally. Compound 19 was the most potent inhibitor of WT EGFR (3.0 nM) observed, more potent than the EGFR WT inhibitor Erlotinib (5.9 nM). Compounds 48 and 49 demonstrated better activity for the double-mutant EGFR (3.0 & 2.0 nM, respectively) than Osimertinib (12.8 nM). The selectivity of these compounds for the DM was found to be comparable to Osimertinib (∼20 fold) while their phosphate buffer solubilities were > 50-fold better than both marketed drugs. Kinetic evaluation of 48 (propenamide moiety) vs 49 (acrylamide electrophile) confirms k<inf>inact</inf>/K<inf>i</inf> values consistent with a covalent mode of action for the latter, but not the former. 2009 Elsevier Ltd. All rights reserved.
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Insights into the EGFR SAR of N-phenylquinazolin-4-amine-derivatives using quantum mechanical pairwise-interaction energies
(2019-08-01)
Simeon, Saw
;
Jongkon, Nathjanan
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Chotpatiwetchkul, Warot
;
Gleeson, M. Paul
Protein kinases are an important class of enzymes that play an essential role in virtually all major disease areas. In addition, they account for approximately 50% of the current targets pursued in drug discovery research. In this work, we explore the generation of structure-based quantum mechanical (QM) quantitative structure–activity relationship models (QSAR) as a means to facilitate structure-guided optimization of protein kinase inhibitors. We explore whether more accurate, interpretable QSAR models can be generated for a series of 76 N-phenylquinazolin-4-amine inhibitors of epidermal growth factor receptor (EGFR) kinase by comparing and contrasting them to other standard QSAR methodologies. The QM-based method involved molecular docking of inhibitors followed by their QM optimization within a ~ 300 atom cluster model of the EGFR active site at the M062X/6-31G(d,p) level. Pairwise computations of the interaction energies with each active site residue were performed. QSAR models were generated by splitting the datasets 75:25 into a training and test set followed by modelling using partial least squares (PLS). Additional QSAR models were generated using alignment dependent CoMFA and CoMSIA methods as well as alignment independent physicochemical, e-state indices and fingerprint descriptors. The structure-based QM-QSAR model displayed good performance on the training and test sets (r<sup>2</sup> ~ 0.7) and was demonstrably more predictive than the QSAR models built using other methods. The descriptor coefficients from the QM-QSAR models allowed for a detailed rationalization of the active site SAR, which has implications for subsequent design iterations.
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A theoretical study of cis-trans isomerisation in H-ZSM5: Probing the impact of cluster size and zeolite framework on energetics and structure
(2008-01-01)
Gleeson, Duangkamol
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). © Springer Science+Business Media B.V. 2008.
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The catalytic conversion of acetonitrile to acrylonitrile in zeolitic systems: Rationalization of experimental observations using theoretical simulations
(2007-12-15)
Gleeson, Duangkamol
;
Limtrakul, Jumras
Quantum mechanical calculations have been performed on faujasite and silicalite models to investigate reported experimental differences in yields of two key catalytic products (propionitrile and acrylonitrile) formed from the reaction of acetonitrile with either methanol or formaldehyde, respectively. The calculations were performed using 12T and 10T cluster representations of faujasite and silicalite, respectively, and the results are in good overall agreement with experimental observations. Both reactions are predicted to proceed in a concerted manner, with the transfer of a proton to the basic zeolite oxygen atom in conjunction with the methyl group migration to form a reaction intermediate. The stationary points found on the reaction surface in both zeolites have been systematically assessed using principal components analysis to give us an insight into the correlated nature of the structural/electronic changes that occur on the reaction surfaces. © 2007 Elsevier B.V. All rights reserved.

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