Fragment Molecular Orbital Method Applied to Lead Optimization of Novel Interleukin-2 Inducible T-Cell Kinase (ITK) Inhibitors

Heifetz, Alexander; Trani, Giancarlo; Aldeghi, Matteo; MacKinnon, Colin H.; McEwan, Paul; Brookfield, Frederick A.; Chudyk, Ewa I.; Bodkin, Michael J.; Pei, Zhonghua; Burch, Jason D.; Ortwine, Daniel F.

doi:10.1021/acs.jmedchem.6b00045

Cited by 71 publications

(81 citation statements)

References 45 publications

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“…This observation is consistent with previous trends for the QM method to predict stronger hydrogen bonds. Our findings corresponded to the attraction energy distribution calculated previously by Heifetz et al for all GPCR‐A crystal structures, which indicated equal electrostatic and hydrophobic character of the orthosteric binding pockets located in the transmembrane‐units …”

Section: Discussionsupporting

confidence: 91%

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ONIOM and FMO‐EDA study of metabotropic glutamate receptor 1: Quantum insights into the allosteric binding site

Śliwa

Kurczab

Bojarski

2018

Int J of Quantum Chemistry

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The crystal structure of metabotropic glutamate receptor 1 (mGluR1) complexed with 4‐fluoro‐N‐(4‐(6‐(isopropylamino)pyrimidin‐4‐yl)thiazol‐2‐yl)‐N‐methylbenzamide (FITM, a negative allosteric modulator) and its twelve close structural analogs with a broad spectrum of affinities (2.4 nM < IC50 > 10 000 nM) were investigated using quantum mechanical methods. The our own N‐layered integrated molecular orbital and molecular mechanics (ONIOM) was used to optimize the molecular geometries of the receptor with complexed ligands, which were then used to perform the ab initio calculations using the fragment molecular orbitals method with energy decomposition analysis (FMO‐EDA). The results clearly showed that residues Q6603.28 and/or Y8056.55 were the anchoring points for all the studied analogs of FITM, while the H‐bond with T8157.38 determined only the orientation of very active molecules containing an amino substituent in the pyrimidine moiety (e.g., FITM). The orientation of the other parts of ligands resulted from hydrophobic interactions mainly with L7575.44, F8016.51, or W7986.48. The applied ONIOM/FMO–EDA approach facilitated the study of effects related to very small changes in the ligand structure and led to conclusions regarding the significance of individual interactions in the allosteric binding pocket of mGluR1.

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Section: Discussionsupporting

confidence: 91%

“…The FMO calculations were performed for the ligand and all residues located approximately 4 Å from the ligand. This procedure has been applied successfully to GPCRs by other authors . The FMO input options were set as default.…”

Section: Methodsmentioning

confidence: 99%

ONIOM and FMO‐EDA study of metabotropic glutamate receptor 1: Quantum insights into the allosteric binding site

Śliwa

Kurczab

Bojarski

2018

Int J of Quantum Chemistry

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“…The FMO methodology was successfully applied to various large biological systems, primarily in a retrospective analysis of binding sites [5][6][7][8][9][10][11][12][13][14][15][16], but also as a tool supporting drug design [17][18][19][20]. Among these, several studies [7,11,16,18] have focused on one of the most important groups of biological targets, a G protein-coupled receptors (GPCRs) family. The authors found crucial interactions that were often ignored by structure-based descriptions and indicated that the FMO scheme would be a valuable tool for structure-based drug design by estimations of the chemical character of the proteins binding site.…”

Section: Introductionmentioning

confidence: 99%

Recognition of repulsive and attractive regions of selected serotonin receptor binding site using FMO-EDA approach

et al. 2019

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The complexes of selected long-chain arylpiperazines with homology models of 5-HT 1A , 5-HT 2A , and 5-HT 7 receptors were investigated using quantum mechanical methods. The molecular geometries of the ligand-receptor complexes were firstly optimized with the Our own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM) method. Next, the fragment molecular orbitals method with an energy decomposition analysis scheme (FMO-EDA) was employed to estimate the interaction energies in binding sites. The results clearly showed that orthosteric binding sites of studied serotonin receptors have both attractive and repulsive regions. In the case of 5-HT 1A and 5-HT 2A two repulsive areas, located in the lower part of the binding pocket, and one large area of attraction engaging many residues at the top of all helices were identified. Additionally, for the 5-HT 7 receptor, the third area of destabilization located at the extracellular end of the helix 6 was found.

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“…Recently, an approximate molecular orbital (MO) method called Fragment Molecular Orbital (FMO) was implemented into studies related to GPCR-ligand interactions [60][61][62][63][64][65][66][67][68]. FMO has been described in previous publications and review articles [60][61][62].…”

Section: The Qm Approach In Gpcr Studiesmentioning

confidence: 99%

Multiscale Molecular Modeling in G Protein-Coupled Receptor (GPCR)-Ligand Studies

et al. 2020

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G protein-coupled receptors (GPCRs) are major drug targets due to their ability to facilitate signal transduction across cell membranes, a process that is vital for many physiological functions to occur. The development of computational technology provides modern tools that permit accurate studies of the structures and properties of large chemical systems, such as enzymes and GPCRs, at the molecular level. The advent of multiscale molecular modeling permits the implementation of multiple levels of theories on a system of interest, for instance, assigning chemically relevant regions to high quantum mechanics (QM) level of theory while treating the rest of the system using classical force field (molecular mechanics (MM) potential). Multiscale QM/MM molecular modeling have far-reaching applications in the rational design of GPCR drugs/ligands by affording precise ligand binding configurations through the consideration of conformational plasticity. This enables the identification of key binding site residues that could be targeted to manipulate GPCR function. This review will focus on recent applications of multiscale QM/MM molecular simulations in GPCR studies that could boost the efficiency of future structure-based drug design (SBDD) strategies.

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Fragment Molecular Orbital Method Applied to Lead Optimization of Novel Interleukin-2 Inducible T-Cell Kinase (ITK) Inhibitors

Cited by 71 publications

References 45 publications

ONIOM and FMO‐EDA study of metabotropic glutamate receptor 1: Quantum insights into the allosteric binding site

ONIOM and FMO‐EDA study of metabotropic glutamate receptor 1: Quantum insights into the allosteric binding site

Recognition of repulsive and attractive regions of selected serotonin receptor binding site using FMO-EDA approach

Multiscale Molecular Modeling in G Protein-Coupled Receptor (GPCR)-Ligand Studies

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