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Article: [In-Silico Drug Discovery Support-Current Situation and Challenges].

Hirokawa, Takatsugu

Gan to kagaku ryoho. Cancer & chemotherapy

2022 Volume 49, Issue 4, Page(s) 359–364

Abstract: In the drug discovery field, the current problems are sluggish drug development due to the depletion of target molecules and other factors, and rising development costs. In silico drug discovery is expected to be a drug discovery support technology that ... ...

Abstract	In the drug discovery field, the current problems are sluggish drug development due to the depletion of target molecules and other factors, and rising development costs. In silico drug discovery is expected to be a drug discovery support technology that will lead to the discovery of novel drug target molecules, active sites, lead compounds to more efficient development processes. In silico drug discovery can be broadly classified into methods directed by ligand information(ligand-based drug design: LBDD)and methods based on the 3-dimensional structure of target proteins(structure-based drug design: SBDD). LBDD method is based on similar structural and physicochemical properties in overall structure, or substructures and pharmacophore, using known ligands information, and has the advantage that it can be applied even when the 3-dimensional structure of the target protein is unknown. On the other hand, SBDD is a method to discovery and design compounds directed to the 3-dimensional structure of the target protein based on the'lock and key'theory, in which the target protein selects and binds to specific ligands, and has the advantage of leading to the discovery of diversity compounds. This paper outlines the basics of LBDD and SBDD, and the latest topics using AI and large-scale simulations. Furthermore, as an example of in-silico drug discovery support, in-silico drug discovery support research for the discovery of protein-protein interaction inhibitors targeting early-stage lung adenocarcinoma is also introduced.
MeSH term(s)	Drug Design ; Drug Discovery/methods ; Humans ; Ligands ; Proteins
Chemical Substances	Ligands ; Proteins
Language	Japanese
Publishing date	2022-04-20
Publishing country	Japan
Document type	Journal Article
ZDB-ID	604842-0
ISSN	0385-0684
ISSN	0385-0684
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Article ; Online: Lipid bilayer membrane permeability mechanism of the K-Ras(G12D)-inhibitory bicyclic peptide KS-58 elucidated by molecular dynamics simulations.

Sakamoto, Kotaro / Hirokawa, Takatsugu

Bioorganic & medicinal chemistry letters

2024 Volume 100, Page(s) 129649

Abstract: Peptides are mid-size molecules (700-2000 g/mol) and have attracted particular interest as therapeutic modalities as they are superior in controlling protein-protein interactions, a process that is a typical drug target category, compared with small ... ...

Abstract	Peptides are mid-size molecules (700-2000 g/mol) and have attracted particular interest as therapeutic modalities as they are superior in controlling protein-protein interactions, a process that is a typical drug target category, compared with small molecules (<500 g/mol). In 2020, we identified KS-58 (1333 g/mol) as a K-Ras(G12D)-inhibitory bicyclic peptide and suggested its cell membrane permeability. However, the membrane permeability mechanism had not been elucidated. In this study, we aim to clarify the mechanism by molecular dynamics (MD) simulations. Initially, we simulated the molecular conformations of KS-58 in water (a polar solvent) and in chloroform (a non-polar solvent). The identified stable conformations were significantly different in each solvent. KS-58 behaves as a chameleon-like molecule as it alters its polar surface area (PSA) depending on the solvent environment. It was also discovered that orientation of Asp's side chain is a critical energy barrier for KS-58 altering its conformation from hydrophilic to lipophilic. Taking these properties into consideration, we simulated its lipid bilayer membrane permeability. KS-58 shifted toward the inside of the lipid bilayer membrane with altering its conformations to lipophilic. When the simulation condition was set in deionized form of that carboxy group of Asp, KS-58 traveled deeper inside the cell membrane. PSA and the depth of the membrane penetration correlated. In vitro data suggested that cell membrane permeability of KS-58 is improved in weakly acidic conditions leading to partial deionization of the carboxy group. Our data provide an example of the molecular properties of mid-size peptides with membrane accessibility and propose an effective metadynamics approach to elucidate such molecular mechanisms by MD simulations.
MeSH term(s)	Lipid Bilayers/chemistry ; Molecular Dynamics Simulation ; Peptides/chemistry ; Solvents/chemistry ; Permeability ; Peptides, Cyclic
Chemical Substances	Lipid Bilayers ; KS-58 ; Peptides ; Solvents ; Peptides, Cyclic
Language	English
Publishing date	2024-02-09
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2024.129649
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Article ; Online: Structural and Energetic Basis for Differential Binding of Ebola and Marburg Virus Glycoproteins to a Bat-Derived Niemann-Pick C1 Protein.

Igarashi, Manabu / Hirokawa, Takatsugu / Takada, Ayato

The Journal of infectious diseases

2023 Volume 228, Issue Suppl 7, Page(s) S479–S487

Abstract: Background: Our previous study demonstrated that the fruit bat (Yaeyama flying fox)-derived cell line FBKT1 showed preferential susceptibility to Ebola virus (EBOV), whereas the human cell line HEK293T was similarly susceptible to EBOV and Marburg virus ...

Abstract	Background: Our previous study demonstrated that the fruit bat (Yaeyama flying fox)-derived cell line FBKT1 showed preferential susceptibility to Ebola virus (EBOV), whereas the human cell line HEK293T was similarly susceptible to EBOV and Marburg virus (MARV). This was due to 3 amino acid differences of the endosomal receptor Niemann-Pick C1 (NPC1) between FBKT1 and HEK293T (ie, TET and SGA, respectively, at positions 425-427), as well as 2 amino acid differences at positions 87 and 142 of the viral glycoprotein (GP) between EBOV and MARV. Methods/results: To understand the contribution of these amino acid differences to interactions between NPC1 and GP, we performed molecular dynamics simulations and binding free energy calculations. The average binding free energies of human NPC1 (hNPC1) and its mutant having TET at positions 425-427 (hNPC1/TET) were similar for the interaction with EBOV GP. In contrast, hNPC1/TET had a weaker interaction with MARV GP than wild-type hNPC1. As expected, substitutions of amino acid residues at 87 or 142 in EBOV and MARV GPs converted the binding affinity to hNPC1/TET. Conclusions: Our data provide structural and energetic insights for understanding potential differences in the GP-NPC1 interaction, which could influence the host tropism of EBOV and MARV.
MeSH term(s)	Animals ; Humans ; Hemorrhagic Fever, Ebola ; Niemann-Pick C1 Protein ; Marburgvirus/metabolism ; Chiroptera ; HEK293 Cells ; Virus Internalization ; Glycoproteins/metabolism ; Ebolavirus/metabolism ; Amino Acids
Chemical Substances	Niemann-Pick C1 Protein ; Glycoproteins ; Amino Acids
Language	English
Publishing date	2023-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiad120
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Article ; Online: AAp-MSMD: Amino Acid Preference Mapping on Protein-Protein Interaction Surfaces Using Mixed-Solvent Molecular Dynamics.

Kudo, Genki / Yanagisawa, Keisuke / Yoshino, Ryunosuke / Hirokawa, Takatsugu

Journal of chemical information and modeling

2023 Volume 63, Issue 24, Page(s) 7768–7777

Abstract: Peptides have attracted much attention recently owing to their well-balanced properties as drugs against protein-protein interaction (PPI) surfaces. Molecular simulation-based predictions of binding sites and amino acid residues with high affinity to PPI ...

Abstract	Peptides have attracted much attention recently owing to their well-balanced properties as drugs against protein-protein interaction (PPI) surfaces. Molecular simulation-based predictions of binding sites and amino acid residues with high affinity to PPI surfaces are expected to accelerate the design of peptide drugs. Mixed-solvent molecular dynamics (MSMD), which adds probe molecules or fragments of functional groups as solutes to the hydration model, detects the binding hotspots and cryptic sites induced by small molecules. The detection results vary depending on the type of probe molecule; thus, they provide important information for drug design. For rational peptide drug design using MSMD, we proposed MSMD with amino acid residue probes, named amino acid probe-based MSMD (AAp-MSMD), to detect hotspots and identify favorable amino acid types on protein surfaces to which peptide drugs bind. We assessed our method in terms of hotspot detection at the amino acid probe level and binding free energy prediction with amino acid probes at the PPI site for the complex structure that formed the PPI. In hotspot detection, the max-spatial probability distribution map (max-PMAP) obtained from AAp-MSMD detected the PPI site, to which each type of amino acid can bind favorably. In the binding free energy prediction using amino acid probes, ΔGFE obtained from AAp-MSMD roughly estimated the experimental binding affinities from the structure-activity relationship. AAp-MSMD, with amino acid probes, provides estimated binding sites and favorable amino acid types at the PPI site of a target protein.
MeSH term(s)	Molecular Dynamics Simulation ; Solvents/chemistry ; Amino Acids/metabolism ; Proteins/chemistry ; Binding Sites ; Peptides/chemistry ; Protein Binding
Chemical Substances	Solvents ; Amino Acids ; Proteins ; Peptides
Language	English
Publishing date	2023-12-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.3c01677
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Article ; Online: Protein druggability assessment for natural products using in silico simulation: A case study with estrogen receptor and the flavonoid genistein.

Ohbuchi, Katsuya / Hirokawa, Takatsugu

Gene

2021 Volume 791, Page(s) 145726

Abstract: Traditional herbal medicine (THM) comprises a vast number of natural compounds. Most of them are metabolized into different structures after administration, which makes the clarification of THM's mode of action more complicated. To evaluate the ... ...

Abstract	Traditional herbal medicine (THM) comprises a vast number of natural compounds. Most of them are metabolized into different structures after administration, which makes the clarification of THM's mode of action more complicated. To evaluate the biological activities of those components and metabolites, in silico simulation technology is helpful. We focused on mixed-solvent molecular dynamics (MD) simulation for druggability assessment of natural products. Mixed-solvent MD is an in silico simulation method for the exploration of ligand-binding sites on target proteins, which uses water and an organic molecule mixture. The selection of organic small molecules is an important factor for predicting the characteristics of natural products. In this study, we used the known crystal structure of estrogen receptors with genistein as a test case and explored fragments reflecting the characteristics of natural products. We found that structures with a 4-pyrone structure are more often included in the natural products database compared with the DrugBank database, and we selectively detected the known-binding sites of estrogen receptor α and β. The results indicate that the 4-pyrone structure might be promising for predicting the protein druggability of flavonoids. Additionally, mixed-solvent MD simulation discriminates the selectivity of genistein between estrogen receptor β and α, indicating that the simulation can be evaluated using indices that differ from those of traditional ligand docking. Although this approach is still in its early stages, it has the potential to provide valuable information for understanding the diverse biological activities of natural products.
MeSH term(s)	Animals ; Binding Sites/drug effects ; Biological Products/chemistry ; Computer Simulation ; Databases, Factual ; Estrogen Receptor alpha/chemistry ; Estrogen Receptor alpha/metabolism ; Estrogen Receptor beta/chemistry ; Estrogen Receptor beta/metabolism ; Flavonoids/chemistry ; Genistein/pharmacology ; Humans ; Ligands ; Medicine, Traditional/methods ; Molecular Docking Simulation/methods ; Molecular Dynamics Simulation ; Plants, Medicinal/chemistry ; Plants, Medicinal/metabolism ; Protein Binding/drug effects ; Receptors, Estrogen/chemistry
Chemical Substances	Biological Products ; Estrogen Receptor alpha ; Estrogen Receptor beta ; Flavonoids ; Ligands ; Receptors, Estrogen ; Genistein (DH2M523P0H)
Language	English
Publishing date	2021-05-16
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2021.145726
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Article ; Online: Biological Evaluation of Isosteric Applicability of 1,3-Substituted Cuneanes as m-Substituted Benzenes Enabled by Selective Isomerization of 1,4-Substituted Cubanes.

Fujiwara, Kan / Nagasawa, Shota / Maeyama, Ryusei / Segawa, Ryosuke / Hirasawa, Noriyasu / Hirokawa, Takatsugu / Iwabuchi, Yoshiharu

Chemistry (Weinheim an der Bergstrasse, Germany)

2024 Volume 30, Issue 11, Page(s) e202303548

Abstract: We herein evaluate a biological applicability of 1,3-substituted cuneanes as an isostere of m-substituted benzenes based on its structural similarity. An investigation of a method to obtain 1,3-substituted cuneanes by selective isomerization of 1,4- ... ...

Abstract	We herein evaluate a biological applicability of 1,3-substituted cuneanes as an isostere of m-substituted benzenes based on its structural similarity. An investigation of a method to obtain 1,3-substituted cuneanes by selective isomerization of 1,4-substituted cubanes enables this attempt by giving a key synthetic step to obtain a cuneane analogs of pharmaceuticals having m-substituted benzene moiety. Biological evaluation of the synthesized analogs and in silico study of the obtained result revealed a potential usage of cuneane skeleton in medicinal chemistry.
MeSH term(s)	Benzene/chemistry ; Isomerism ; Benzene Derivatives/chemistry
Chemical Substances	Benzene (J64922108F) ; Benzene Derivatives
Language	English
Publishing date	2024-01-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1478547-X
ISSN	1521-3765 ; 0947-6539
ISSN (online)	1521-3765
ISSN	0947-6539
DOI	10.1002/chem.202303548
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Article: Protein druggability assessment for natural products using in silico simulation: A case study with estrogen receptor and the flavonoid genistein

Ohbuchi, Katsuya / Hirokawa, Takatsugu

Gene. 2021 July 30, v. 791

2021

Abstract: Traditional herbal medicine (THM) comprises a vast number of natural compounds. Most of them are metabolized into different structures after administration, which makes the clarification of THM’s mode of action more complicated. To evaluate the ... ...

Abstract	Traditional herbal medicine (THM) comprises a vast number of natural compounds. Most of them are metabolized into different structures after administration, which makes the clarification of THM’s mode of action more complicated. To evaluate the biological activities of those components and metabolites, in silico simulation technology is helpful. We focused on mixed-solvent molecular dynamics (MD) simulation for druggability assessment of natural products. Mixed-solvent MD is an in silico simulation method for the exploration of ligand-binding sites on target proteins, which uses water and an organic molecule mixture. The selection of organic small molecules is an important factor for predicting the characteristics of natural products. In this study, we used the known crystal structure of estrogen receptors with genistein as a test case and explored fragments reflecting the characteristics of natural products. We found that structures with a 4-pyrone structure are more often included in the natural products database compared with the DrugBank database, and we selectively detected the known-binding sites of estrogen receptor α and β. The results indicate that the 4-pyrone structure might be promising for predicting the protein druggability of flavonoids. Additionally, mixed-solvent MD simulation discriminates the selectivity of genistein between estrogen receptor β and α, indicating that the simulation can be evaluated using indices that differ from those of traditional ligand docking. Although this approach is still in its early stages, it has the potential to provide valuable information for understanding the diverse biological activities of natural products.
Keywords	case studies ; computer simulation ; crystal structure ; databases ; estrogen receptors ; estrogens ; genes ; genistein ; herbal medicines ; ligands ; mechanism of action ; metabolites ; molecular dynamics
Language	English
Dates of publication	2021-0730
Publishing place	Elsevier B.V.
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2021.145726
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Article ; Online: Pocket to concavity: a tool for the refinement of protein-ligand binding site shape from alpha spheres.

Kudo, Genki / Hirao, Takumi / Yoshino, Ryunosuke / Shigeta, Yasuteru / Hirokawa, Takatsugu

Bioinformatics (Oxford, England)

2023 Volume 39, Issue 4

Abstract: Summary: Understanding the binding site of the target protein is essential for rational drug design. Pocket detection software predicts the ligand binding site of the target protein; however, the predicted protein pockets are often excessively estimated ...

Abstract	Summary: Understanding the binding site of the target protein is essential for rational drug design. Pocket detection software predicts the ligand binding site of the target protein; however, the predicted protein pockets are often excessively estimated in comparison with the actual volume of the bound ligands. This study proposes a refinement tool for the pockets predicted by an alpha sphere-based approach, Pocket to Concavity (P2C). P2C is divided into two modes: Ligand-Free (LF) and Ligand-Bound (LB) modes. The LF mode provides the shape of the deep and druggable concavity where the core scaffold can bind. The LB mode searches the deep concavity around the bound ligand. Thus, P2C is useful for identifying and designing desirable compounds in Structure-Based Drug Design (SBDD). Availability and implementation: Pocket to Concavity is freely available at https://github.com/genki-kudo/Pocket-to-Concavity. This tool is implemented in Python3 and Fpocket2.
MeSH term(s)	Protein Conformation ; Proteins/chemistry ; Binding Sites ; Protein Binding ; Software ; Ligands
Chemical Substances	Proteins ; Ligands
Language	English
Publishing date	2023-04-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btad212
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Article ; Online: Chemosynthetic ethanolamine plasmalogen stimulates gonadotropin secretion from bovine gonadotrophs by acting as a potential GPR61 agonist.

Kadokawa, Hiroya / Yoshino, Ryunosuke / Saito, Risa / Hirokawa, Takatsugu

Animal reproduction science

2022 Volume 241, Page(s) 106992

Abstract: Brain ethanolamine plasmalogens (EPls) are unique alkenylacyl-glycerophospholipids and the only recognized ligands of G-protein-coupled receptor 61 (GPR61), a newly identified receptor that colocalizes with GnRH receptors on gonadotrophs. As the chemical ...

Abstract	Brain ethanolamine plasmalogens (EPls) are unique alkenylacyl-glycerophospholipids and the only recognized ligands of G-protein-coupled receptor 61 (GPR61), a newly identified receptor that colocalizes with GnRH receptors on gonadotrophs. As the chemical synthesis of EPl is challenging, only one chemosynthetic EPl, 1-(1Z-octadecenyl)- 2-oleoyl-sn-glycero-3-phosphoethanolamine (PLAPE; C18:0-C18:1), is commercially available. Therefore, we tested the hypothesis that PLAPE stimulates gonadotropin secretion from bovine gonadotrophs. We prepared anterior pituitary cells from healthy, post-pubertal heifers, cultured for 3.5 d, and then treated them with increasing concentrations (0, 0.5, 5, 50, or 500 pg/mL) of PLAPE for 5 mi, before either no treatment or GnRH stimulation. After 2 h, medium samples were harvested for FSH and LH assays. PLAPE (5-500 pg/mL) stimulated (P < 0.01) basal FSH and LH secretion, and such stimulation effects were inhibited by a SMAD pathway inhibitor. In the presence of GnRH, PLAPE at 0.5 and 5 pg/mL stimulated FSH and LH secretion (P < 0.01). However, a higher dose of PLAPE (500 pg/mL) suppressed GnRH-induced FSH and LH, and such suppressive effects were inhibited by an ERK pathway inhibitor. PLAPE stimulated gonadotropin secretion in the presence of EPls extracted from the brains of young heifers, but not old cows. Additionally, we performed in silico molecular-docking simulations using the deep-learning algorithm, AlphaFold2. The simulations revealed the presence of three binding sites for PLAPE in the three-dimensional structural model of GPR61. In conclusion, PLAPE stimulated gonadotropin secretion from bovine gonadotrophs and might act as a chemosynthetic agonist of GPR61.
MeSH term(s)	Animals ; Cattle ; Female ; Follicle Stimulating Hormone/metabolism ; Follicle Stimulating Hormone/pharmacology ; Gonadotrophs/metabolism ; Gonadotropin-Releasing Hormone/metabolism ; Gonadotropin-Releasing Hormone/pharmacology ; Plasmalogens/metabolism ; Plasmalogens/pharmacology
Chemical Substances	Plasmalogens ; phosphatidal ethanolamines ; Gonadotropin-Releasing Hormone (33515-09-2) ; Follicle Stimulating Hormone (9002-68-0)
Language	English
Publishing date	2022-05-13
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	429674-6
ISSN	1873-2232 ; 0378-4320
ISSN (online)	1873-2232
ISSN	0378-4320
DOI	10.1016/j.anireprosci.2022.106992
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Article ; Online: Inverse Mixed-Solvent Molecular Dynamics for Visualization of the Residue Interaction Profile of Molecular Probes.

Yanagisawa, Keisuke / Yoshino, Ryunosuke / Kudo, Genki / Hirokawa, Takatsugu

International journal of molecular sciences

2022 Volume 23, Issue 9

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.
MeSH term(s)	Ligands ; Molecular Dynamics Simulation ; Molecular Probes ; Proteins/chemistry ; Solvents/chemistry
Chemical Substances	Ligands ; Molecular Probes ; Proteins ; Solvents
Language	English
Publishing date	2022-04-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23094749
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