Molecular principle of the cyclin-dependent kinase selectivity of 4-(thiazol-5-yl)-2-(phenylamino) pyrimidine-5-carbonitrile derivatives revealed by molecular modeling studies

Kong, Xiaotian; Sun, Huiyong; Pan, Peichen; Tian, Sheng; Li, Dan; Li, Youyong; Hou, Tingjun

doi:10.1039/c5cp05622e

Cited by 21 publications

(20 citation statements)

References 68 publications

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“…According to previous studies, US simulations can also accurately rank the binding affinities of different inhibitor–protein systems . As shown in Table , it can be observed that the PMF values of the four systems are −20.12, −15.10, −15.15, and −12.93 kcal mol −1 , respectively, which is in satisfactory agreement with the experimental date.…”

Section: Resultssupporting

confidence: 79%

“…The calculated binding affinities are much stronger than the experimental data. According to the previous studies, MM/GBSA usually provides reliable ranking results rather than accurately predicting the absolute binding free energies . According to the calculation results, COM25 has the strongest inhibition to GSK3β than CDK2 and its predicted binding free energy for GSK3β is the highest.…”

Section: Resultsmentioning

confidence: 99%

“…The binding free energy (Δ G bind ) for each system was calculated by the MM/GBSA methodology according to Equation

\begin{matrix} Δ G_{normalbind} & = G_{normalcomplex} - G_{normalprotein} - G_{normalligand} \\ = Δ H + Δ G_{normalsolvation} - T Δ S \\ = Δ E_{normalMM} + Δ G_{normalGB} + Δ G_{normalSA} - T Δ S \end{matrix}

where Δ E MM is the gas‐phase interaction energy between protein and ligand, including the electrostatic (Δ E ele ) and van der Waals interactions (Δ E vdw ); Δ G GB and Δ G SA are the polar and non‐polar contributions of the solvation free energy, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Umbrella sampling (US) simulations were carried out to characterize the unbinding pathway of each inhibitor from their corresponding targets to illuminate the drug binding selectivity . Firstly, the equilibrated snapshots extracted from the trajectories were used as the initial structures for the US simulations.…”

Section: Methodsmentioning

confidence: 99%

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Theoretical studies on the selective mechanisms of GSK3β and CDK2 by molecular dynamics simulations and free energy calculations

Zhao

Zhu

et al. 2016

Chem Biol Drug Des

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Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinase which is widely involved in cell signaling and controls a broad number of cellular functions. GSK3 contains α and β isoforms, and GSK3β has received more attention and becomes an attractive drug target for the treatment of several diseases. The binding pocket of cyclin-dependent kinase 2 (CDK2) shares high sequence identity to that of GSK3β, and therefore, the design of highly selective inhibitors toward GSK3β remains a big challenge. In this study, a computational strategy, which combines molecular docking, molecular dynamics simulations, free energy calculations, and umbrella sampling simulations, was employed to explore the binding mechanisms of two selective inhibitors to GSK3β and CDK2. The simulation results highlighted the key residues critical for GSK3β selectivity. It was observed that although GSK3β and CDK2 share the conserved ATP-binding pockets, some different residues have significant contributions to protein selectivity. This study provides valuable information for understanding the GSK3β-selective binding mechanisms and the rational design of selective GSK3β inhibitors.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

“…The binding free energy (Δ G bind ) for each system was calculated by the MM/GBSA methodology according to Equation

\begin{matrix} Δ G_{normalbind} & = G_{normalcomplex} - G_{normalprotein} - G_{normalligand} \\ = Δ H + Δ G_{normalsolvation} - T Δ S \\ = Δ E_{normalMM} + Δ G_{normalGB} + Δ G_{normalSA} - T Δ S \end{matrix}

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Theoretical studies on the selective mechanisms of GSK3β and CDK2 by molecular dynamics simulations and free energy calculations

Zhao

Zhu

et al. 2016

Chem Biol Drug Des

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show abstract

“…MM/GBSA method is a practical approach in current computer-aided drug design field which can balance accuracy and speed. [62,[71][72][73][74][75] Although deviation is inevitable when MM/GBSA method is utilized for free energy calculation due to its approximation processing, this bias is eliminated when comparing free energy of different ligands to the same target. [76,77] This method is still very popular and is used by many researchers because of its good correlation with the experimental values.…”

Section: Binding Free Energy and Decomposition Analysismentioning

confidence: 99%

Covalent vs. Non‐Covalent Inhibition: Tackling Drug Resistance in EGFR – A Thorough Dynamic Perspective

Akher

Farrokhzadeh

Soliman

2019

Chemistry & Biodiversity

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A persistent challenge in the treatment of non‐small cell lung cancer (NSCLC) with EGFR is the emergence of drug‐resistant caused by somatic mutations. The EGFR L858R/T790 M double mutant (EGFRDM) was found to be the most alarming variant. Despite the development of a wide range of inhibitors, none of them could inhibit EGFRDM effectively. Recently, 11h and 45a, have been found to be potent inhibitors against EGFRDM through two distinctive mechanisms, non‐covalent and covalent binding, respectively. However, the structural and dynamic implications of the two modes of inhibitions remain unexplored. Herein, two molecular dynamics simulation protocols, coupled with free‐energy calculations, were applied to gain insight into the atomistic nature of each binding mode. The comparative analysis confirmed that there is a significant difference in the binding free energy between 11h and 45a (ΔΔGbind=−21.17 kcal/mol). The main binding force that governs the binding of both inhibitors is vdW, with a higher contribution for 45a. Two residues ARG841 and THR854 were found to have curtailed role in the binding of 45a to EGFRDM by stabilizing its flexible alcohol chain. The 45a binding to EGFRDM induces structural rearrangement in the active site to allow easier accessibility of 45a to target residue CYS797. The findings of this work can substantially shed light on new strategies for developing novel classes of covalent and non‐covalent inhibitors with increased specificity and potency.

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Computational modeling studies reveal the origin of the binding preference of 3‐(3,4‐di hydroisoquinolin‐2(1H)‐ylsulfonyl)benzoic acids for AKR1C3 over its isoforms

Kong

Xing

et al. 2022

Protein Science

Self Cite

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As a key regulator for hormone activity, human aldo‐keto reductase family 1 member C3 (AKR1C3) plays crucial roles in the occurrence of various hormone‐dependent or independent malignancies. It is a promising target for treating castration‐resistant prostate cancer (CRPC). However, the development of AKR1C3 specific inhibitors remains challenging due to the high sequence similarity to its isoform AKR1C2. Here, we performed a combined in silico study to illuminate the inhibitory preference of 3‐(3,4‐dihydroisoquinolin‐2(1H)‐ylsulfonyl)benzoic acids for AKR1C3 over AKR1C2, of which compound 38 can achieve up to 5000‐fold anti‐AKR1C3 selectivity. Our umbrella sampling (US) simulations together with end‐point binding free energy calculation MM/GBSA uncover that the high inhibition selectivity originates from the different binding modes, namely “Inward” and “Outward,” of this compound series in AKR1C3 and AKR1C2, respectively. In AKR1C3/38, the tetrahydroquinoline moiety of 38 is accommodated inside the SP1 pocket and interacts favorably with surrounding residues, while, in AKR1C2/38, the SP1 pocket is too small to hold the bulky tetrahydroquinoline group that instead moves out of the pocket with 38 transitioning from an “Inward” to an “Outward” state. Further 3D‐QSAR and energy decomposition analyses suggest that SP1 in AKR1C3 prefers to bind with a rigid bicyclic moiety and the modification of the R3 group has important implication for the compound's activity. This work is the first attempt to elucidate the selectivity mechanism of inhibitors toward AKR1C3 at the atomic level, which is anticipated to propel the development of next‐generation AKR1C3 inhibitors with enhanced efficacy and reduced “off‐target” effect for CRPC therapy.

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Molecular principle of the cyclin-dependent kinase selectivity of 4-(thiazol-5-yl)-2-(phenylamino) pyrimidine-5-carbonitrile derivatives revealed by molecular modeling studies

Cited by 21 publications

References 68 publications

Theoretical studies on the selective mechanisms of GSK3β and CDK2 by molecular dynamics simulations and free energy calculations

Theoretical studies on the selective mechanisms of GSK3β and CDK2 by molecular dynamics simulations and free energy calculations

Covalent vs. Non‐Covalent Inhibition: Tackling Drug Resistance in EGFR – A Thorough Dynamic Perspective

Computational modeling studies reveal the origin of the binding preference of 3‐(3,4‐di hydroisoquinolin‐2(1H)‐ylsulfonyl)benzoic acids for AKR1C3 over its isoforms

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