scholarly journals Aromatic Rings as Molecular Determinants for the Molecular Recognition of Protein Kinase Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1776
Author(s):  
Yan Zhu ◽  
Saad Alqahtani ◽  
Xiche Hu
Keyword(s):  
Hydrogen Bonding ◽  
Molecular Recognition ◽  
Protein Kinases ◽  
Aromatic Ring ◽  
Kinase Inhibitors ◽  
Binding Pocket ◽  
Atp Binding ◽  
Aromatic Rings ◽  
Π Interactions ◽  
Molecular Determinants

Protein kinases are key enzymes in many signal transduction pathways, and play a crucial role in cellular proliferation, differentiation, and various cell regulatory processes. However, aberrant function of kinases has been associated with cancers and many other diseases. Consequently, competitive inhibition of the ATP binding site of protein kinases has emerged as an effective means of curing these diseases. Over the past three decades, thousands of protein kinase inhibitors (PKIs) with varying molecular frames have been developed. Large-scale data mining of the Protein Data Bank resulted in a database of 2139 non-redundant high-resolution X-ray crystal structures of PKIs bound to protein kinases. This provided us with a unique opportunity to study molecular determinants for the molecular recognition of PKIs. A chemoinformatic analysis of 2139 PKIs resulted in findings that PKIs are “flat” molecules with high aromatic ring counts and low fractions of sp3 carbon. All but one PKI possessed one or more aromatic rings. More importantly, it was found that the average weighted hydrogen bond count is inversely proportional to the number of aromatic rings. Based on this linear relationship, we put forward the exchange rule of hydrogen bonding interactions and non-bonded π-interactions. Specifically, a loss of binding affinity caused by a decrease in hydrogen bonding interactions is compensated by a gain in binding affinity acquired by an increase in aromatic ring-originated non-bonded interactions (i.e., π–π stacking interactions, CH–π interactions, cation–π interactions, etc.), and vice versa. The very existence of this inverse relationship strongly suggests that both hydrogen bonding and aromatic ring-originated non-bonded interactions are responsible for the molecular recognition of PKIs. As an illustration, two representative PKI–kinase complexes were employed to examine the relative importance of different modes of non-bonded interactions for the molecular recognition of PKIs. For this purpose, two FDA-approved PKI drugs, ibrutinib and lenvatinib, were chosen. The binding pockets of both PKIs were thoroughly examined to identify all non-bonded intermolecular interactions. Subsequently, the strengths of interaction energies between ibrutinib and its interacting residues in tyrosine kinase BTK were quantified by means of the double hybrid DFT method B2PLYP. The resulting energetics for the binding of ibrutinib in tyrosine kinase BTK showed that CH–π interactions and π–π stacking interactions between aromatic rings of the drug and hydrophobic residues in its binding pocket dominate the binding interactions. Thus, this work establishes that, in addition to hydrogen bonding, aromatic rings function as important molecular determinants for the molecular recognition of PKIs. In conclusion, our findings support the following pharmacophore model for ATP-competitive kinase inhibitors: a small molecule features a scaffold of one or more aromatic rings which is linked with one or more hydrophilic functional groups. The former has the structural role of acting as a scaffold and the functional role of participating in aromatic ring-originated non-bonded interactions with multiple hydrophobic regions in the ATP binding pocket of kinases. The latter ensure water solubility and form hydrogen bonds with the hinge region and other hydrophilic residues of the ATP binding pocket.

scholarly journals Allosteric inhibition of Aurora-A kinase by a synthetic VNAR nanobody

2016 ◽  
Author(s):  
Selena G. Burgess ◽  
Arkadiusz Oleksy ◽  
Tommaso Cavazza ◽  
Mark W. Richards ◽  
Isabelle Vernos ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Kinase Inhibitors ◽  
Catalytic Domain ◽  
Binding Pocket ◽  
Protein Kinase Inhibitors ◽  
Single Domain ◽  
Atp Binding ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Allosteric Site

AbstractThe vast majority of clinically-approved protein kinase inhibitors target the ATP binding pocket directly. Consequently, many inhibitors have broad selectivity profiles and most have significant off-target effects. Allosteric inhibitors are generally more selective, but are difficult to identify because allosteric binding sites are often unknown or poorly characterized, and there is no clearly preferred approach to generating hit matter. Aurora-A is activated through binding of TPX2 to an allosteric site on the kinase catalytic domain, and this knowledge could be exploited to generate an inhibitor. However, it is currently unclear how to design such a compound because a small molecule or peptide mimetic of TPX2 would be expected to activate, not inhibit the kinase. Here, we generated an allosteric inhibitor of Aurora-A kinase based on a synthetic, VNAR single domain nanobody scaffold, IgNARV-D01. Biochemical studies and a crystal structure of the Aurora-A/IgNARV-D01 complex show that the nanobody overlaps with the TPX2 binding site. In contrast with the binding of TPX2, which stabilizes an active conformation of the kinase, binding of the nanobody stabilizes an inactive conformation, in which the αC-helix is distorted, the canonical Lys-Glu salt bridge is broken, and the regulatory (R-) spine is disrupted by an additional hydrophobic side chain from the activation loop. These studies illustrate how nanobodies can be used to characterize the regulatory mechanisms of kinases and provide a rational basis for structure-guided design of allosteric Aurora-A kinase inhibitors.SignificanceProtein kinases are commonly dysregulated in cancer and inhibitors of protein kinases are key therapeutic drugs. However, this strategy is often undermined by a lack of selectivity since the ATP binding pocket that kinase inhibitors usually target is highly conserved. Inhibitors that target allosteric sites are more selective but more difficult to generate. Here we identify a single domain antibody (nanobody) to target an allosteric pocket on the catalytic domain of Aurora-A kinase and demonstrate that the mechanism is antagonistic to a physiologically-relevant allosteric activator, TPX2. This work will enable the development of allosteric Aurora-A inhibitors as potential therapeutics, and provide a model for the development of tools to investigate allosteric modes of kinase inhibition.

scholarly journals Crizotinib acts as ABL1 inhibitor combining ATP-binding with allosteric inhibition and is active against native BCR-ABL1 and its resistance and compound mutants BCR-ABL1T315I and BCR-ABL1T315I-E255K

2021 ◽  
Author(s):  
Afsar Ali Mian ◽  
Isabella Haberbosch ◽  
Hazem Khamaisie ◽  
Abed Agbarya ◽  
Larissa Pietsch ◽  
...  
Keyword(s):  
Binding Site ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Binding Pocket ◽  
Atp Binding ◽  
Atp Binding Site ◽  
Lung Cancer Patients

AbstractResistance remains the major clinical challenge for the therapy of Philadelphia chromosome–positive (Ph+) leukemia. With the exception of ponatinib, all approved tyrosine kinase inhibitors (TKIs) are unable to inhibit the common “gatekeeper” mutation T315I. Here we investigated the therapeutic potential of crizotinib, a TKI approved for targeting ALK and ROS1 in non-small cell lung cancer patients, which inhibited also the ABL1 kinase in cell-free systems, for the treatment of advanced and therapy-resistant Ph+ leukemia. By inhibiting the BCR-ABL1 kinase, crizotinib efficiently suppressed growth of Ph+ cells without affecting growth of Ph− cells. It was also active in Ph+ patient-derived long-term cultures (PD-LTCs) independently of the responsiveness/resistance to other TKIs. The efficacy of crizotinib was confirmed in vivo in syngeneic mouse models of BCR-ABL1- or BCR-ABL1T315I-driven chronic myeloid leukemia–like disease and in BCR-ABL1-driven acute lymphoblastic leukemia (ALL). Although crizotinib binds to the ATP-binding site, it also allosterically affected the myristol binding pocket, the binding site of GNF2 and asciminib (former ABL001). Therefore, crizotinib has a seemingly unique double mechanism of action, on the ATP-binding site and on the myristoylation binding pocket. These findings strongly suggest the clinical evaluation of crizotinib for the treatment of advanced and therapy-resistant Ph+ leukemia.

Exploration of relative π-electron localization in naphthalene aromatic rings by C–H⋯π interactions: experimental evidence, computational criteria, and database analysis

CrystEngComm ◽  
2019 ◽  
Vol 21 (42) ◽  
pp. 6432-6445 ◽  
Author(s):  
Ali Samie ◽  
Alireza Salimi ◽  
Jered C. Garrison
Keyword(s):  
Experimental Evidence ◽  
Aromatic Ring ◽  
Electron Localization ◽  
Aromatic Rings ◽  
Database Analysis ◽  
Π Interactions ◽  
Contact Position

In C–H⋯π interaction, the relative π-electron localization in aromatic ring led to the change of contact position from centre to edges of the ring (C–H⋯πe) which was confirmed by experimental evidences, computational criteria, and database analysis.

scholarly journals Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket

2013 ◽  
Vol 289 (7) ◽  
pp. 4432-4443 ◽  
Author(s):  
Shih-Chia Tso ◽  
Xiangbing Qi ◽  
Wen-Jun Gui ◽  
Cheng-Yang Wu ◽  
Jacinta L. Chuang ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Kinase Inhibitors ◽  
Binding Pocket ◽  
Pyruvate Dehydrogenase Kinase ◽  
Atp Binding

In vitro and in vivo activity of regorafenib (REGO) in drug-resistant gastrointestinal stromal tumors (GIST).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10510-10510 ◽  
Author(s):  
Cesar Serrano-Garcia ◽  
Michael C. Heinrich ◽  
Meijun Zhu ◽  
Chandrajit P. Raut ◽  
Grant Eilers ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Initial Response ◽  
Binding Pocket ◽  
Atp Binding ◽  
Activation Loop ◽  
Line Therapy ◽  
Exon 11 ◽  
Clinical Trial Results

10510 Background: KIT and PDGFRA mutations (mut) are the crucial transforming events in most GISTs, and tyrosine kinase inhibitors (TKIs) with activity against KIT and PDGFRA, such as imatinib (IM) (front-line therapy) and sunitinib (SU) (second-line therapy), are effective treatments in GIST patients (pts). Resistance to IM and SU is commonly associated with evolution of secondary kinase mut. REGO is a multi-targeted TKI that inhibits KIT, PDGFR, and other oncologic targets and has recently shown benefit in pts with metastatic GIST after progression on standard treatments. We evaluated the in vitro and in vivo activity of REGO compared with IM, SU, and sorafenib (SOR) (a multi-TKI structurally related to REGO). Methods: REGO, IM, SU, and SOR inhibition of viability and KIT phosphorylation was assessed in human GIST cell lines and in Ba/F3 cells transformed by KIT oncoproteins with IM-resistant ATP binding pocket or activation-loop mut. KIT/PDGFRA genotyping was performed in GISTs responding or progressing on REGO in the academic phase II clinical trial. Results: In GISTs with KIT exon 11 mutant oncoproteins, REGO potently inhibited viability, KIT phosphorylation, and downstream effector phosphorylation (AKT, MAPK, S6). IM-resistant activation loop mut were more potently inhibited by REGO than SU, whereas the gatekeeper IM-resistant mut T670I was inhibited by both REGO and SU, and the common ATP-binding pocket mutant V654A was more potently inhibited by SU than REGO. Two GIST metastases progressing in one pt after initial response to REGO contained KIT V654A mut. SOR and REGO demonstrated comparable in vitro overall activity. Representative GIST cell line viability IC50s are shown in the Table (values in bold indicate expected clinical relevance). Conclusions: In vitro studies confirm REGO is a potent inhibitor of KIT exon 11 mut in GIST and appears to have stronger activity than SU against the most common KIT activation-loop mut observed in GIST. Ongoing clinical correlative analyses from REGO-treated study patients will be presented. [Table: see text]

scholarly journals The gatekeeper residue and beyond: homologous calcium-dependent protein kinases as drug development targets for veterinarian Apicomplexa parasites

Parasitology ◽  
2014 ◽  
Vol 141 (11) ◽  
pp. 1499-1509 ◽  
Author(s):  
KATELYN R. KEYLOUN ◽  
MOLLY C. REID ◽  
RYAN CHOI ◽  
YIFAN SONG ◽  
ANNA M. W. FOX ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Kinases ◽  
Kinase Inhibitors ◽  
Neospora Caninum ◽  
Babesia Bovis ◽  
Atp Binding ◽  
Calcium Dependent ◽  
Binding Cavity ◽  
Dependent Protein ◽  
Calcium Dependent Protein Kinases

SUMMARYSpecific roles of individual CDPKs vary, but in general they mediate essential biological functions necessary for parasite survival. A comparative analysis of the structure-activity relationships (SAR) of Neospora caninum, Eimeria tenella and Babesia bovis calcium-dependent protein kinases (CDPKs) together with those of Plasmodium falciparum, Cryptosporidium parvum and Toxoplasma gondii was performed by screening against 333 bumped kinase inhibitors (BKIs). Structural modelling and experimental data revealed that residues other than the gatekeeper influence compound–protein interactions resulting in distinct sensitivity profiles. We subsequently defined potential amino-acid structural influences within the ATP-binding cavity for each orthologue necessary for consideration in the development of broad-spectrum apicomplexan CDPK inhibitors. Although the BKI library was developed for specific inhibition of glycine gatekeeper CDPKs combined with low inhibition of threonine gatekeeper human SRC kinase, some library compounds exhibit activity against serine- or threonine-containing CDPKs. Divergent BKI sensitivity of CDPK homologues could be explained on the basis of differences in the size and orientation of the hydrophobic pocket and specific variation at other amino-acid positions within the ATP-binding cavity. In particular, BbCDPK4 and PfCDPK1 are sensitive to a larger fraction of compounds than EtCDPK1 despite the presence of a threonine gatekeeper in all three CDPKs.

Signatures of the ATP-binding pocket as a basis for structural classification of the serine/threonine protein kinases of gram-positive bacteria

2012 ◽  
Vol 80 (5) ◽  
pp. 1363-1376 ◽  
Author(s):  
Natalia V. Zakharevich ◽  
Dmitry I. Osolodkin ◽  
Irena I. Artamonova ◽  
Vladimir A. Palyulin ◽  
Nikolay S. Zefirov ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Binding Pocket ◽  
Atp Binding ◽  
Structural Classification ◽  
Gram Positive ◽  
Gram Positive Bacteria

scholarly journals Design and Synthesis of Potent and Selective PIM Kinase Inhibitors by Targeting Unique Structure of ATP-Binding Pocket

2017 ◽  
Vol 8 (5) ◽  
pp. 504-509 ◽  
Author(s):  
Hirofumi Nakano ◽  
Tsukasa Hasegawa ◽  
Hirotatsu Kojima ◽  
Takayoshi Okabe ◽  
Tetsuo Nagano
Keyword(s):  
Kinase Inhibitors ◽  
Binding Pocket ◽  
Atp Binding ◽  
Design And Synthesis ◽  
Unique Structure

scholarly journals Targeting the trypanosome kinetochore with CLK1 protein kinase inhibitors

2019 ◽  
Author(s):  
Manuel Saldivia ◽  
Srinivasa P.S. Rao ◽  
Eric Fang ◽  
Elmarie Myburgh ◽  
Elaine Brown ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Competitive Inhibition ◽  
Binding Pocket ◽  
Protein Kinase Inhibitors ◽  
Kinetochore Assembly ◽  
Phenotypic Screen ◽  
Novel Drug

ABSTRACTThe kinetochore is a macromolecular structure that assembles on the centromeres of chromosomes and provides the major attachment point for spindle microtubules during mitosis. In Trypanosoma brucei the proteins that make up the kinetochore are highly divergent, with the inner kinetochore comprising at least 20 distinct and essential proteins (KKT1-20) that include four protein kinases, CLK1 (KKT10), CLK2 (KKT19), KKT2 and KKT3. We performed a phenotypic screen of T. brucei bloodstream forms with a Novartis kinase-focused inhibitor library, which identified a number of selective inhibitors with potent pan-kinetoplastid activity. Deconvolution of an amidobenzimidazole series using a selection of 37 T. brucei mutants that over-express known essential protein kinases identified CLK1 as the primary target. Biochemical studies show that the irreversible competitive inhibition of CLK1 is dependent on a Michael acceptor forming an irreversible bond with C215 in the ATP binding pocket, a residue that is not present in human CLK1, thereby providing selectivity. Chemical inhibition of CLK1 impairs inner kinetochore recruitment and compromises cell cycle progression, leading to cell death. We show that KKT2 is a substrate for CLK1 and identify phosphorylation of S508 to be essential for KKT2 function and for kinetochore assembly. We propose that CLK1 is part of a novel signalling cascade that controls kinetochore function via phosphorylation of the inner kinetochore protein kinase KKT2. This work highlights a novel drug target for trypanosomatid parasitic protozoa and a new chemical tool for investigating the function of their divergent kinetochores.

scholarly journals Crystal structure of 9,9′-{(1E,1′E)-[1,4-phenylenebis(azanylylidene)]bis(methanylylidene)}bis(2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-8-ol)

2016 ◽  
Vol 72 (10) ◽  
pp. 1366-1369 ◽  
Author(s):  
Md. Serajul Haque Faizi ◽  
Akram Ali ◽  
Vadim A. Potaskalov
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bonds ◽  
Benzene Ring ◽  
Aromatic Ring ◽  
Title Compound ◽  
Inversion Symmetry ◽  
Inversion Center ◽  
Aromatic Rings ◽  
Π Interactions ◽  
Compound C

The whole molecule of the title compound, C32H34N2O2, is generated by inversion symmetry; the central benzene ring being situated about the crystallographic inversion center. The aromatic ring of the julolidine moiety is inclined to the central benzene ring by 33.70 (12)°. There are two intramolecular O—H...N hydrogen bonds in the molecule, generatingS(6) ring motifs. The conformation about the C=N bonds isE. The fused non-aromatic rings of the julolidine moiety adopt half-chair conformations. In the crystal, adjacent molecules are linked by pairs of C—H...π interactions, forming a ladder-like structure propagating along thea-axis direction.

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