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Article ; Online: Identification of a novel CDK9 inhibitor targeting the intramolecular hidden cavity of CDK9 induced by Tat binding.

Kaori Asamitsu / Takatsugu Hirokawa / Takashi Okamoto

PLoS ONE, Vol 17, Iss 11, p e

2022 Volume 0277024

Abstract: HIV-1 transcription is specifically augmented by a transcriptional activator complex composed of Tat, an HIV-1-encoded activator, and the host transcription elongation factor P-TEFb, which is composed of cyclin-dependent kinase 9 (CDK9) and cyclin T1. ... ...

Abstract	HIV-1 transcription is specifically augmented by a transcriptional activator complex composed of Tat, an HIV-1-encoded activator, and the host transcription elongation factor P-TEFb, which is composed of cyclin-dependent kinase 9 (CDK9) and cyclin T1. Several observations suggest that P-TEFb is an attractive anti-HIV-1 drug target. However, the long-term cytotoxicity of CDK9 inhibitors hinders their widespread use in HIV-1 therapy. Thus, novel and safe inhibitors are sorely needed. By performing molecular dynamics simulations of the 3D structure of Tat/P-TEFb, we previously identified a unique cavity structure of CDK9, the CDK9 hidden cavity, that is specifically induced by Tat binding. Here, we attempted to identify compounds that fit this cavity and inhibit CDK9 activity by in silico screening. We identified compounds that could inhibit CDK9 activity. One of such compound, 127, showed the strongest inhibitory activity against CDK9. Interestingly, it also inhibited CDK6 to a similar extent. We inspected the amino acid sequence and structural properties of the CDK9 hidden cavity to determine whether it is conserved in other CDKs, such as CDK6. The Ile61, comprising the center of the CDK9 hidden cavity, appears to be crucial for its kinase activity, thus indicating that the identification of the CDK9 hidden cavity may provide vital information for the development of novel CDK9 inhibitors.
Keywords	Medicine ; R ; Science ; Q
Subject code	540
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Inverse Mixed-Solvent Molecular Dynamics for Visualization of the Residue Interaction Profile of Molecular Probes

Keisuke Yanagisawa / Ryunosuke Yoshino / Genki Kudo / Takatsugu Hirokawa

International Journal of Molecular Sciences, Vol 23, Iss 4749, p

2022 Volume 4749

Abstract: To ensure efficiency in discovery and development, the application of computational technology is essential. Although virtual screening techniques are widely applied in the early stages of drug discovery research, the computational methods used in lead ... ...

Abstract	To ensure efficiency in discovery and development, the application of computational technology is essential. Although virtual screening techniques are widely applied in the early stages of drug discovery research, the computational methods used in lead optimization to improve activity and reduce the toxicity of compounds are still evolving. In this study, we propose a method to construct the residue interaction profile of the chemical structure used in the lead optimization by performing “inverse” mixed-solvent molecular dynamics (MSMD) simulation. Contrary to constructing a protein-based, atom interaction profile, we constructed a probe-based, protein residue interaction profile using MSMD trajectories. It provides us the profile of the preferred protein environments of probes without co-crystallized structures. We assessed the method using three probes: benzamidine, catechol, and benzene. As a result, the residue interaction profile of each probe obtained by MSMD was a reasonable physicochemical description of the general non-covalent interaction. Moreover, comparison with the X-ray structure containing each probe as a ligand shows that the map of the interaction profile matches the arrangement of amino acid residues in the X-ray structure.
Keywords	mixed-solvent molecular dynamics ; interaction pattern analysis ; residue interaction profile ; visualization ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	541
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Quantitative comparison of protein-protein interaction interface using physicochemical feature-based descriptors of surface patches

Woong-Hee Shin / Keiko Kumazawa / Kenichiro Imai / Takatsugu Hirokawa / Daisuke Kihara

Frontiers in Molecular Biosciences, Vol

2023 Volume 10

Abstract: Driving mechanisms of many biological functions in a cell include physical interactions of proteins. As protein-protein interactions (PPIs) are also important in disease development, protein-protein interactions are highlighted in the pharmaceutical ... ...

Abstract	Driving mechanisms of many biological functions in a cell include physical interactions of proteins. As protein-protein interactions (PPIs) are also important in disease development, protein-protein interactions are highlighted in the pharmaceutical industry as possible therapeutic targets in recent years. To understand the variety of protein-protein interactions in a proteome, it is essential to establish a method that can identify similarity and dissimilarity between protein-protein interactions for inferring the binding of similar molecules, including drugs and other proteins. In this study, we developed a novel method, protein-protein interaction-Surfer, which compares and quantifies similarity of local surface regions of protein-protein interactions. protein-protein interaction-Surfer represents a protein-protein interaction surface with overlapping surface patches, each of which is described with a three-dimensional Zernike descriptor (3DZD), a compact mathematical representation of 3D function. 3DZD captures both the 3D shape and physicochemical properties of the protein surface. The performance of protein-protein interaction-Surfer was benchmarked on datasets of protein-protein interactions, where we were able to show that protein-protein interaction-Surfer finds similar potential drug binding regions that do not share sequence and structure similarity. protein-protein interaction-Surfer is available at https://kiharalab.org/ppi-surfer.
Keywords	protein-protein interaction ; PPI ; PPI drugs ; molecular surface ; protein-protein interaction (PPI) ; 3D Zernike descriptor ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo

Kotaro Sakamoto / Teruaki Masutani / Takatsugu Hirokawa

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 16

Abstract: Abstract Ras mutations (e.g., occur in K-Ras, N-Ras, and H-Ras) are one of the most desirable and promising drug targets in chemotherapy treatments for cancer. However, there are still no approved drugs directly targeting mutated Ras. In 2017, an ... ...

Abstract	Abstract Ras mutations (e.g., occur in K-Ras, N-Ras, and H-Ras) are one of the most desirable and promising drug targets in chemotherapy treatments for cancer. However, there are still no approved drugs directly targeting mutated Ras. In 2017, an artificial cyclic peptide, KRpep-2d, was discovered as the first selective inhibitor of K-Ras(G12D), the most frequent K-Ras mutation. Here, we report the generation of KS-58, a KRpep-2d derivative that is identified as a bicyclic peptide and possess unnatural amino acid structures. Our in vitro data and molecular dynamics simulations suggest that KS-58 enters cells and blocks intracellular Ras–effector protein interactions. KS-58 selectively binds to K-Ras(G12D) and suppresses the in vitro proliferation of the human lung cancer cell line A427 and the human pancreatic cancer cell line PANC-1, both of which express K-Ras(G12D). Moreover, KS-58 exhibits anti-cancer activity when given as an intravenous injection to mice with subcutaneous or orthotropic PANC-1 cell xenografts. The anti-cancer activity is further improved by combination with gemcitabine. To the best of our knowledge, this is the first report of K-Ras(G12D)-selective inhibitory peptide presenting in vivo anti-cancer activity. KS-58 is an attractive lead molecule for the development of novel cancer drugs that target K-Ras(G12D).
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: MD simulation of the Tat/Cyclin T1/CDK9 complex revealing the hidden catalytic cavity within the CDK9 molecule upon Tat binding.

Kaori Asamitsu / Takatsugu Hirokawa / Takashi Okamoto

PLoS ONE, Vol 12, Iss 2, p e

2017 Volume 0171727

Abstract: In this study, we applied molecular dynamics (MD) simulation to analyze the dynamic behavior of the Tat/CycT1/CDK9 tri-molecular complex and revealed the structural changes of P-TEFb upon Tat binding. We found that Tat could deliberately change the local ...

Abstract	In this study, we applied molecular dynamics (MD) simulation to analyze the dynamic behavior of the Tat/CycT1/CDK9 tri-molecular complex and revealed the structural changes of P-TEFb upon Tat binding. We found that Tat could deliberately change the local flexibility of CycT1. Although the structural coordinates of the H1 and H2 helices did not substantially change, H1', H2', and H3' exhibited significant changes en masse. Consequently, the CycT1 residues involved in Tat binding, namely Tat-recognition residues (TRRs), lost their flexibility with the addition of Tat to P-TEFb. In addition, we clarified the structural variation of CDK9 in complex with CycT1 in the presence or absence of Tat. Interestingly, Tat addition significantly reduced the structural variability of the T-loop, thus consolidating the structural integrity of P-TEFb. Finally, we deciphered the formation of the hidden catalytic cavity of CDK9 upon Tat binding. MD simulation revealed that the PITALRE signature sequence of CDK9 flips the inactive kinase cavity of CDK9 into the active form by connecting with Thr186, which is crucial for its activity, thus presumably recruiting the substrate peptide such as the C-terminal domain of RNA pol II. These findings provide vital information for the development of effective novel anti-HIV drugs with CDK9 catalytic activity as the target.
Keywords	Medicine ; R ; Science ; Q
Subject code	540
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Evaluating cepharanthine analogues as natural drugs against SARS‐CoV‐2

Atsushi Hijikata / Clara Shionyu‐Mitsuyama / Setsu Nakae / Masafumi Shionyu / Motonori Ota / Shigehiko Kanaya / Takatsugu Hirokawa / Shogo Nakajima / Koichi Watashi / Tsuyoshi Shirai

FEBS Open Bio, Vol 12, Iss 1, Pp 285-

2022 Volume 294

Abstract: Cepharanthine (CEP) is a natural biscoclaurine alkaloid of plant origin and was recently demonstrated to have anti‐severe acute respiratory syndrome coronavirus 2 (anti‐SARS‐CoV‐2) activity. In this study, we evaluated whether natural analogues of CEP ... ...

Abstract	Cepharanthine (CEP) is a natural biscoclaurine alkaloid of plant origin and was recently demonstrated to have anti‐severe acute respiratory syndrome coronavirus 2 (anti‐SARS‐CoV‐2) activity. In this study, we evaluated whether natural analogues of CEP may act as potential anti‐coronavirus disease 2019 drugs. A total of 24 compounds resembling CEP were extracted from the KNApSAcK database, and their binding affinities to target proteins, including the spike protein and main protease of SARS‐CoV‐2, NPC1 and TPC2 in humans, were predicted via molecular docking simulations. Selected analogues were further evaluated by a cell‐based SARS‐CoV‐2 infection assay. In addition, the efficacies of CEP and its analogue tetrandrine were assessed. A comparison of the docking conformations of these compounds suggested that the diphenyl ester moiety of the molecules was a putative pharmacophore of the CEP analogues.
Keywords	coronavirus ; drug repurposing ; molecular docking ; natural drug ; SARS‐CoV ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Molecular dynamics simulation and experimental verification of the interaction between cyclin T1 and HIV-1 Tat proteins.

Kaori Asamitsu / Takatsugu Hirokawa / Yurina Hibi / Takashi Okamoto

PLoS ONE, Vol 10, Iss 3, p e

2015 Volume 0119451

Abstract: The viral encoded Tat protein is essential for the transcriptional activation of HIV proviral DNA. Interaction of Tat with a cellular transcription elongation factor P-TEFb containing CycT1 is critically required for its action. In this study, we ... ...

Abstract	The viral encoded Tat protein is essential for the transcriptional activation of HIV proviral DNA. Interaction of Tat with a cellular transcription elongation factor P-TEFb containing CycT1 is critically required for its action. In this study, we performed MD simulation using the 3D data for wild-type and 4CycT1mutants3D data. We found that the dynamic structural change of CycT1 H2' helix is indispensable for its activity for the Tat action. Moreover, we detected flexible structural changes of the Tat-recognition cavity in the WT CycT1 comprising of ten AAs that are in contact with Tat. These structural fluctuations in WT were lost in the CycT1 mutants. We also found the critical importance of the hydrogen bond network involving H1, H1' and H2 helices of CycT1. Since similar AA substitutions of the Tat-CycT1 chimera retained the Tat-supporting activity, these interactions are considered primarily involved in interaction with Tat. These findings described in this paper should provide vital information for the development of effective anti-Tat compound.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: 2-Carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition

Keiko Fukasawa / Mari Gotoh / Akiharu Uwamizu / Takatsugu Hirokawa / Masaki Ishikawa / Yoshibumi Shimizu / Shinji Yamamoto / Kensuke Iwasa / Keisuke Yoshikawa / Junken Aoki / Kimiko Murakami-Murofushi

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 11

Abstract: Abstract Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator that, along with its chemically stabilized analogue 2-carba-cyclic phosphatidic acid (2ccPA), induces various biological activities in vitro and in vivo. Although cPA ... ...

Abstract	Abstract Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator that, along with its chemically stabilized analogue 2-carba-cyclic phosphatidic acid (2ccPA), induces various biological activities in vitro and in vivo. Although cPA is similar to lysophosphatidic acid (LPA) in structure and synthetic pathway, some of cPA biological functions apparently differ from those reported for LPA. We previously investigated the pharmacokinetic profile of 2ccPA, which was found to be rapidly degraded, especially in acidic conditions, yielding an unidentified compound. Thus, not only cPA but also its degradation compound may contribute to the biological activity of cPA, at least for 2ccPA. In this study, we determined the structure and examined the biological activities of 2-carba-lysophosphatidic acid (2carbaLPA) as a 2ccPA degradation compound, which is a type of β-LPA analogue. Similar to LPA and cPA, 2carbaLPA induced the phosphorylation of the extracellular signal-regulated kinase and showed potent agonism for all known LPA receptors (LPA1–6) in the transforming growth factor-α (TGFα) shedding assay, in particular for LPA3 and LPA4. 2carbaLPA inhibited the lysophospholipase D activity of autotaxin (ATX) in vitro similar to other cPA analogues, such as 2ccPA, 3-carba-cPA, and 3-carba-LPA (α-LPA analogue). Our study shows that 2carbaLPA is a novel β-LPA analogue with high potential for the activation of some LPA receptors and ATX inhibition.
Keywords	Medicine ; R ; Science ; Q
Subject code	540
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural insights into the differences among lactisole derivatives in inhibitory mechanisms against the human sweet taste receptor.

Tomoya Nakagita / Akiko Ishida / Takumi Matsuya / Takuya Kobayashi / Masataka Narukawa / Takatsugu Hirokawa / Makoto Hashimoto / Takumi Misaka

PLoS ONE, Vol 14, Iss 3, p e

2019 Volume 0213552

Abstract: Lactisole, an inhibitor of the human sweet taste receptor, has a 2-phenoxypropionic acid skeleton and has been shown to interact with the transmembrane domain of the T1R3 subunit (T1R3-TMD) of the receptor. Another inhibitor, 2,4-DP, which shares the ... ...

Abstract	Lactisole, an inhibitor of the human sweet taste receptor, has a 2-phenoxypropionic acid skeleton and has been shown to interact with the transmembrane domain of the T1R3 subunit (T1R3-TMD) of the receptor. Another inhibitor, 2,4-DP, which shares the same molecular skeleton as lactisole, was confirmed to be approximately 10-fold more potent in its inhibitory activity than lactisole; however the structural basis of their inhibitory mechanisms against the receptor remains to be elucidated. Crystal structures of the TMD of metabotropic glutamate receptors, which along with T1Rs are categorized as class C G-protein coupled receptors, have recently been reported and made it possible to create an accurate structural model for T1R3-TMD. In this study, the detailed structural mechanism underlying sweet taste inhibition was characterized by comparing the action of lactisole on T1R3-TMD with that of 2,4-DP. We first performed a series of experiments using cultured cells expressing the sweet taste receptor with mutations and examined the interactions with these inhibitors. Based on the results, we next performed docking simulations and then applied molecular dynamics-based energy minimization. Our analyses clearly revealed that the (S)-isomers of both lactisole and 2,4-DP, interacted with the same seven residues in T1R3-TMD and that the inhibitory potencies of those inhibitors were mainly due to stabilizing interactions mediated via their carboxyl groups in the vertical dimension of the ligand pocket of T1R3-TMD. In addition, 2,4-DP engaged in a hydrophobic interaction mediated by its o-Cl group, and this interaction may be chiefly responsible for the higher inhibitory potency of 2,4-DP.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Synthesis and Telomeric G-Quadruplex-Stabilizing Ability of Macrocyclic Hexaoxazoles Bearing Three Side Chains

Yue Ma / Keisuke Iida / Shogo Sasaki / Takatsugu Hirokawa / Brahim Heddi / Anh Tuân Phan / Kazuo Nagasawa

Molecules, Vol 24, Iss 2, p

2019 Volume 263

Abstract: G-quadruplexes (G4s), which are structures formed in guanine-rich regions of DNA, are involved in a variety of significant biological functions, and therefore “sequence-dependent” selective G4-stabilizing agents are required as tools to investigate and ... ...

Abstract	G-quadruplexes (G4s), which are structures formed in guanine-rich regions of DNA, are involved in a variety of significant biological functions, and therefore “sequence-dependent” selective G4-stabilizing agents are required as tools to investigate and modulate these functions. Here, we describe the synthesis of a new series of macrocyclic hexaoxazole-type G4 ligand (6OTD) bearing three side chains. One of these ligands, 5b, stabilizes telomeric G4 preferentially over the G4-forming DNA sequences of c-kit and K-ras, due to the interaction of its piperazinylalkyl side chain with the groove of telomeric G4.
Keywords	macrocyclic oxazole ; G-quadruplex ; telomere ; telomestatin ; Organic chemistry ; QD241-441
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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