The importance of CH/π hydrogen bonds in rational drug design: An ab initio fragment molecular orbital study to leukocyte-specific protein tyrosine (LCK) kinase

Ozawa, Tomonaga; Tsuji, Eiichi; Ozawa, Motoyasu; Handa, Chiaki; Mukaiyama, Harunobu; Nishimura, Toshihiro; Kobayashi, Satoko; Okazaki, Kosuke

doi:10.1016/j.bmc.2008.10.041

Cited by 61 publications

(42 citation statements)

References 51 publications

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“…[26] The FMO method has been applied to many biomolecular systems to describe protein-ligand interaction in detail. [27,28] Here, to analyze the contribution from each amino acid residue to the interaction, we employed the FMO method as implemented in GAMESS to calculate the interaction energy of bisphosphonate compounds for FPPS. In the FMO method, a protein is divided into fragments based on the amino acid unit (Fig.…”

Section: Interaction Analysis By Fmo Calculation Of Fpps With N-bpsmentioning

confidence: 99%

Computational Insights into Binding of Bisphosphates to Farnesyl Pyrophosphate Synthase

Ohno

Mori

Orita

et al. 2011

CMC

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Bisphosphonates (BPs) are the most widely used and effective treatment for osteoporosis and Paget's disease. Non-nitrogen containing BPs (non-N-BPs), namely etidronate, clodronate, tiludronate, as well as nitrogen-containing BPs (N-BPs), namely pamidronate, alendronate, ibandronate, risedronate, zoledronate and minodronate have been launched on the market to date. N-BPs act by inhibiting the enzyme farnesyl pyrophosphate synthase (FPPS), and several crystal structures of complexes between FPPS and N-BPs have been revealed. Understanding the physical basis of the binding between protein and small molecules is an important goal in both medicinal chemistry and structural biology. In this review, we analyze in detail the energetic basis of molecular recognition between FPPS and N-BPs. First, we summarize the interactions between ligands and proteins observed in N-BPs-FPPS complexes in the Protein Data Bank (PDB). Second, we present an interaction energy analysis on the basis of full quantum mechanical calculation of FPPS and N-BP complexes using the fragment molecular orbital (FMO) method. The FMO result revealed that not only hydrogen bond and electrostatic interaction but also CH-O and π-π interaction with FPPS are important for N-BP’s potency. Third, we describe a binding site analysis of FPPS on the basis of the inhomogeneous solvation theory which, by clustering the results from an explicit solvent molecular dynamics simulation (MD), is capable of describing the entropic and enthalpic contributions to the free energies of individual hydration sites. Finally, we also discuss the structure-activity relationship (SAR) of the series of minodronate derivatives.

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Section: Interaction Analysis By Fmo Calculation Of Fpps With N-bpsmentioning

confidence: 99%

Computational Insights into Binding of Bisphosphates to Farnesyl Pyrophosphate Synthase

Ohno

Mori

Orita

et al. 2011

CMC

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“…Noncovalent interactions involving π systems play a crucial role in crystal engineering, drug design, and protein–ligand complexation . For example, tetraoxacalix[2]arene[2]triazine was found to form 1:1 anion‐π complexes with the polyatomic anions .…”

Section: Introductionmentioning

confidence: 99%

Prominent enhancing effects of substituents on the strength of π···σ‐hole tetrel bond

Wei

Cheng

et al. 2017

Int J of Quantum Chemistry

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The potential applications of tetrel bonds involving π‐molecules in crystal materials and biological systems have prompted a theoretical investigation of the strength of π···σ‐hole tetrel bond in the systems with acetylene and its derivatives of CH3, AuPH3, Li, and Na as well as benzene as the π electron donors. A weak tetrel bond (ΔE < 15 kJ/mol) is found between acetylene and tetrel donor molecule TH3F (T = C, Si, Ge, Sn, and Pb). All substituents strengthen the π tetrel bond, but the electron‐donating sodium atoms have the largest enhancing effect and the interaction energy is up to about 24 kJ/mol in C2Na2‐CH3F. The electron‐donating ability of the AuPH3 fragment is intermediate between the methyl group and alkali metal atom. The origin of the stability of the π tetrel‐bonded complex is dependent on the nature of the tetrel donor and acceptor molecules and can be regulated by the substituents.

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“…In addition to the polar interactions, the dibenzofuran group participates in hydrophobic interactions with Ile519, Ala517 in the P-loop and Gln559 in the Q-loop. The dibenzofuran group is involved in pi-sigma hydrophobic interaction [30] with Gln559 and two pi-alkyl hydrophobic interactions with Ala517 and Ile 519. The C25 atom of 10a is engaged in alkyl hydrophobic interaction [31] with Arg521 in Q-loop.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, bioactivity, 3D-QSAR studies of novel dibenzofuran derivatives as PTP-MEG2 inhibitors

Wei

Zhang

et al. 2017

Oncotarget

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PTP-MEG2 plays a critical role in the diverse cell signalling processes, so targeting PTP-MEG2 is a promising strategy for various human diseases treatments. In this study, a series of novel dibenzofuran derivatives was synthesized and assayed for their PTP-MEG2 inhibitory activities. 10a with highest inhibitory activity (320 nM) exhibited significant selectivity for PTP-MEG2 over its close homolog SHP2, CDC25 (IC50 > 50 μM). By means of the powerful “HipHop” technique, a 3D-QSAR study was carried out to explore structure activity relationship of these molecules. The generated pharmacophore model revealed that the one RA, three Hyd, and two HBA features play an important role in binding to the active site of the target protein-PTP-MEG2. Docking simulation study indicated that 10a achieved its potency and specificity for PTP-MEG2 by targeting unique nearby peripheral binding pockets and the active site. The absorption, distribution, metabolism and excretion (ADME) predictions showed that the 11 compounds hold high potential to be novel lead compounds for targeting PTP-MEG2. Our findings here can provide a new strategy or useful insights for designing the effective PTP-MEG2 inhibitors.

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The importance of CH/π hydrogen bonds in rational drug design: An ab initio fragment molecular orbital study to leukocyte-specific protein tyrosine (LCK) kinase

Cited by 61 publications

References 51 publications

Computational Insights into Binding of Bisphosphates to Farnesyl Pyrophosphate Synthase

Computational Insights into Binding of Bisphosphates to Farnesyl Pyrophosphate Synthase

Prominent enhancing effects of substituents on the strength of π···σ‐hole tetrel bond

Synthesis, bioactivity, 3D-QSAR studies of novel dibenzofuran derivatives as PTP-MEG2 inhibitors

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