Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Molecules. 2023 May 19;28(10):4197. doi: 10.3390/molecules28104197.

Enhancement of Inhibitory Activity by Combining Allosteric Inhibitors Putatively 
Binding to Different Allosteric Sites on Cathepsin K.

Sato S(1), Yamamoto K(1), Ito M(1), Nishino K(1), Otsuka T(2), Irie K(3), Nagao 
M(1).

Author information:
(1)Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
(2)Department of Applied Chemistry and Biotechnology, Okayama University of 
Science, Okayama 700-0005, Japan.
(3)Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.

BACKGROUND: Cathepsin K, which is involved in bone resorption, is a good target 
for treating osteoporosis, but no clinically approved medicine has been 
developed. Recently, allosteric inhibitors with high specificity and few side 
effects have been attracting attention for use in new medicines.
METHODS: Cathepsin K inhibitors were isolated from the methanol extract of 
Chamaecrista nomame (Leguminosae) using cathepsin K inhibition activity-assisted 
multi-step chromatography. Standard kinetic analysis was employed to examine the 
mechanism of cathepsin K inhibition when an isolated inhibitor and its 
derivative were used. The allosteric binding of these cathepsin K inhibitors was 
supported by a docking study using AutoDock vina. Combinations of allosteric 
cathepsin K inhibitors expected to bind to different allosteric sites were 
examined by means of cathepsin K inhibition assay.
RESULTS: Two types of cathepsin K inhibitors were identified in the methanol 
extract of Chamaecrista nomame. One type consisted of cassiaoccidentalin B and 
torachrysone 8-β-gentiobioside, and inhibited both cathepsin K and B with 
similar inhibitory potential, while the other type of inhibitor consisted of 
pheophytin a, and inhibited cathepsin K but not cathepsin B, suggesting that 
pheophytin a binds to an allosteric site of cathepsin K. Kinetic analysis of 
inhibitory activity suggested that pheophytin a and its derivative, pheophorbide 
b, bind allosterically to cathepsin K. This possibility was supported by a 
docking study on cathepsin K. The cathepsin K inhibitory activity of pheophytin 
a and pheophorbide b was enhanced by combining them with the allosteric 
inhibitors NSC 13345 and NSC94914, which bind to other allosteric sites on 
cathepsin K.
CONCLUSIONS: Different allosteric inhibitors that bind to different sites in 
combination, as shown in this study, may be useful for designing new allosteric 
inhibitory drugs with high specificity and few side effects.

DOI: 10.3390/molecules28104197
PMCID: PMC10221639
PMID: 37241936 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflict of interest.


2. RSC Adv. 2021 Dec 9;11(62):39362-39375. doi: 10.1039/d1ra07661b. eCollection 
2021 Dec 6.

Exploring the therapeutic mechanisms of Cassia glauca in diabetes mellitus 
through network pharmacology, molecular docking and molecular dynamics.

Dwivedi PSR(1), Patil R(2), Khanal P(3), Gurav NS(4), Murade VD(5), Hase DP(6), 
Kalaskar MG(7), Ayyanar M(8), Chikhale RV(9), Gurav SS(10).

Author information:
(1)Department of Pharmacology, NGSM Institute of Pharmaceutical Sciences 
(NGSMIPS), Nitte (Deemed to be University) Mangalore-575018 India.
(2)Sinhgad Technical Education Society's, Sinhgad College of Pharmacy Vadgaon 
(Bk) Pune-411041 Maharashtra India.
(3)Department of Pharmacology and Toxicology, KLE College of Pharmacy Belagavi, 
KLE Academy of Higher Education and Research (KAHER) Belagavi-590010 India 
pukarkhanal58@gmail.com.
(4)Ponda Education Society's Rajaram and Tarabai Bandekar College of Pharmacy 
India.
(5)Department of Chemistry, Padmashri Vikhe Patil College Pravarangar, Loni 
Ahmednagar Maharashtra India.
(6)Department of Pharmacognosy, Amrutvahini College of Pharmacy Sangamner 
Maharashtra India.
(7)R C Patel Institute of Pharmaceutical Education and Research Shirpur India.
(8)Department of Botany, A. V. V. M. Sri Pushpam College (Autonomous), 
Affiliated to Bharathidasan University Poondi Thanjavur India.
(9)School of Pharmacy, University of East Anglia Norwich Research Park Norwich 
UK rupeshchikhale7@gmail.com.
(10)Department of Pharmacognosy and Phytochemistry, Goa College of Pharmacy 
Panaji, Goa University Goa-403001 India shailendra.gurav@nic.in.

Cassia glauca is reported as anti-diabetic medicinal plant and is also used as 
an ethnomedicine. However, its mode of action as an anti-diabetic agent has not 
been clearly elucidated. Hence, the present study investigated the probable 
mechanism of action of C. glauca to manage diabetes mellitus via network 
pharmacology and molecular docking and simulations studies. The reported 
bioactives from C. glauca were retrieved from an open-source database, i.e. 
ChEBI, and their targets were predicted using SwissTargetPrediction. The 
proteins involved in the pathogenesis of diabetes were identified from the 
therapeutic target database. The targets involved in diabetes were enriched in 
STRING, and the pathways involved in diabetes were identified concerning the 
KEGG. Cytoscape was used to construct the network among bioactives, proteins, 
and probably regulated pathways, which were analyzed based on edge count. 
Similarly, molecular docking was performed using the Glide module of the 
Schrodinger suite against majorly targeted proteins with their respective 
ligands. Additionally, the drug-likeness score and ADMET profile of the 
individual bioactives were predicted using MolSoft and admetSAR2.0 respectively. 
The stability of these complexes were further studied via molecular dynamics 
simulations and binding energy calculations. Twenty-three bio-actives were 
retrieved from the ChEBI database in which cassiarin B was predicted to modulate 
the highest number of proteins involved in diabetes mellitus. Similarly, GO 
analysis identified the PI3K-Akt signaling pathway to be primarily regulated by 
modulating the highest number of gene. Likewise, aldose reductase (AKR1B1) was 
majorly targeted via the bioactives of C. glauca. Similarly, docking study 
revealed methyl-3,5-di-O-caffeoylquinate (docking score -9.209) to possess the 
highest binding affinity with AKR1B1. Additionally, drug-likeness prediction 
identified cassiaoccidentalin B to possess the highest drug-likeness score, i.e. 
0.84. The molecular dynamics simulations and the MMGBSA indicate high stability 
and greater binding energy for the methyl-3,5-di-O-caffeoylquinate (ΔG bind = 
-40.33 ± 6.69 kcal mol-1) with AKR1B1, thus complementing results from other 
experiments. The study identified cassiarin B, cassiaoccidentalin B, and 
cinnamtannin A2 as lead hits for the anti-diabetic activity of C. glauca. 
Further, the PI3K-Akt and AKR1B1 were traced as majorly modulated pathway and 
target, respectively.

This journal is © The Royal Society of Chemistry.

DOI: 10.1039/d1ra07661b
PMCID: PMC9044434
PMID: 35492478

Conflict of interest statement: All the authors of this manuscript have no 
conflict of interest in any financial and non-financial means.


3. J Ethnopharmacol. 2021 Nov 15;280:114470. doi: 10.1016/j.jep.2021.114470. Epub
 2021 Jul 27.

Inhibition of α-glucosidase by flavonoids of Cymbopogon citratus (DC) Stapf.

Borges PHO(1), Pedreiro S(2), Baptista SJ(3), Geraldes CFGC(4), Batista MT(5), 
Silva MMC(6), Figueirinha A(7).

Author information:
(1)University of Coimbra, Faculty of Pharmacy of University of Coimbra, Coimbra, 
Portugal.
(2)University of Coimbra, Faculty of Pharmacy of University of Coimbra, Coimbra, 
Portugal; LAQV, REQUIMTE, Faculty of Pharmacy, University of Coimbra, Azinhaga 
de Santa Comba, 3000-548, Coimbra, Portugal.
(3)Center for Nuclear Sciences and Technologies, Instituto Superior Técnico, 
University of Lisbon, Portugal; CNC - Center for Neuroscience and Cell Biology, 
University of Coimbra, Coimbra, Portugal.
(4)Department of Life Sciences, Faculty of Science and Technology, University of 
Coimbra, Coimbra, Portugal; Coimbra Chemistry Center, Faculty of Science and 
Technology, University of Coimbra, Coimbra, Portugal.
(5)University of Coimbra, Faculty of Pharmacy of University of Coimbra, Coimbra, 
Portugal; CIEPQPF, Department of Chemical Engineering, Faculty of Science and 
Technology, University of Coimbra, 3030-790, Coimbra, Portugal.
(6)University of Coimbra, Faculty of Pharmacy of University of Coimbra, Coimbra, 
Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 
Coimbra, Portugal. Electronic address: msilva@ff.uc.pt.
(7)University of Coimbra, Faculty of Pharmacy of University of Coimbra, Coimbra, 
Portugal; LAQV, REQUIMTE, Faculty of Pharmacy, University of Coimbra, Azinhaga 
de Santa Comba, 3000-548, Coimbra, Portugal. Electronic address: 
amfigueirinha@ff.uc.pt.

ETHNOPHARMACOLOGICAL RELEVANCE: Leaves extracts from Cymbopogon citratus (DC) 
Stapf. are widely used in traditional medicine exhibiting several in vivo 
biological activities, including antidiabetic. Several flavonoids, including 
aglycones and glycosides, were reported in this plant and previous studies 
suggested that flavonoids may interact with targets related to diabetes.
AIM OF THE STUDY: Evaluated the hypoglycemic activity of C. citratus flavonoids 
through α-glucosidase inhibition and assess the structure-activity relationship 
using molecular docking studies.
MATERIAL AND METHODS: An infusion of C. citratus leaves and its flavonoid-rich 
fraction were prepared. Five flavonoids from this fraction were isolated and 
structurally characterized by UV spectral analysis with shift reagents, 
HPLC-PDA-ESI/MSn and 1H NMR. The antidiabetic potential of C. citratus infusion, 
its flavonoid-rich fraction, glycosylated flavonoids and aglycones was evaluated 
trough the in vitro inhibition of yeast α-glucosidase. Posteriorly, molecular 
docking of the tested flavonoids was performed to investigate its possible 
interactions with the α-glucosidase pocket.
RESULTS: The infusion of C. citratus, its flavonoid-rich fraction, luteolin and 
five flavone glycosides namely, luteolin 6-C-β-glucopyranoside (isoorientin), 
luteolin 7-O-neohesperidoside (ionicerin), luteolin 7-O-β-glucopyranoside 
(cynaroside), Luteolin 2″-O-rhamnosyl-C-(6-deoxy-ribo-hexos-3-ulosyl) 
(cassiaoccidentalin B), luteolin 
6-C-α-arabinofuranosil-(1→2)-α-L-rhamnopyranoside (kurilesin A) showed higher 
inhibitory activity than the reference drug. This activity increased by the 
addition of a sugar moiety. However, the di-glycosides were less active than 
mono-glycosides. The docking studies showed interactions of sugar moieties and A 
or B rings with the catalytic pocket mainly through hydrogen bonds.
CONCLUSIONS: Our results corroborate the potential of C. citratus as a medicinal 
plant for the treatment of diabetes and revealed that its flavonoid glycosides 
has hypoglycemic effect and can be explored as drug candidates to act as 
α-glucosidase inhibitors in the treatment of diabetes.

Copyright © 2021. Published by Elsevier B.V.

DOI: 10.1016/j.jep.2021.114470
PMID: 34329713 [Indexed for MEDLINE]


4. J Diabetes Metab Disord. 2020 May 28;19(2):683-689. doi: 
10.1007/s40200-020-00538-9. eCollection 2020 Dec.

Gene set enrichment analysis of α-amylase and α-glucosidase inhibitors of Cassia 
glauca.

Ternikar SG(1), Patil MB(2), Pasha I(3), Khanal P(4).

Author information:
(1)Sant Gajanan Maharaj College of Pharmacy Mahagaon, Maharashtra, India.
(2)Department of Pharmacognosy and Phytochemistry, KLE College of Pharmacy, 
Belagavi, KLE Academy of Higher Education and Research (KAHER), Belagavi, 590010 
India.
(3)Department of Pharmacology, Orotta College of Medicine and Health Sciences, 
Asmara University, Asmara, Eritrea.
(4)Department of Pharmacology and Toxicology, KLE College of Pharmacy, Belagavi, 
KLE Academy of Higher Education and Research (KAHER), Belagavi, 590010 India.

BACKGROUND: The present study aimed to evaluate in vitro α-amylase and 
α-glucosidase inhibitory activity of various extracts of Cassia glauca, predict 
the binding affinity of multiple phytoconstituents with both enzymes via in 
silico molecular docking and identify the probably modulated pathways by the 
lead hit.
METHODS: Different extracts of Cassia glauca i.e. acetone, ethanol, and aqueous 
extracts were evaluated for α-amylase and α-glucosidase inhibitory activity 
using in vitro method in which starch and 4-Nitrophenyl β-D-glucopyranoside were 
used as substrate respectively. Similarly, the docking study was performed using 
autodock4 to predict the binding affinity of phytoconstituents with α-amylase 
and α-glucosidase. After docking, ten different poses were obtained for the 
ligand molecule. Among them, the pose of ligand molecule with the lowest binding 
energy was visualized in Discovery Studio 2019.
RESULTS AND CONCLUSION: Among the multiple extracts, the aqueous extract showed 
the highest α-amylase (IC50:652.10 ± 20.09) and α-glucosidase 
(IC50:482.46 ± 8.70) inhibitory activity. Similarly, cassiaoccidentalin B was 
predicted to have the highest binding affinity with both enzymes. The potency of 
aqueous extract to inhibit α-amylase and α-glucosidase could be due to multiple 
water-soluble compounds like saponins, flavonoids, and glycosides.

© Springer Nature Switzerland AG 2020.

DOI: 10.1007/s40200-020-00538-9
PMCID: PMC7843725
PMID: 33520796

Conflict of interest statement: Conflict of interestThe authors declared that 
they have no conflict of interest


5. J Ethnopharmacol. 2016 Feb 3;178:222-8. doi: 10.1016/j.jep.2015.12.016. Epub 
2015 Dec 17.

Polyphenols from Cymbopogon citratus leaves as topical anti-inflammatory agents.

Costa G(1), Ferreira JP(2), Vitorino C(2), Pina ME(3), Sousa JJ(2), Figueiredo 
IV(4), Batista MT(2).

Author information:
(1)Center for Pharmaceutical Studies, Faculty of Pharmacy, University of 
Coimbra, Portugal; Center for Neurosciences and Cell Biology, University of 
Coimbra, Portugal. Electronic address: costagff@gmail.com.
(2)Center for Pharmaceutical Studies, Faculty of Pharmacy, University of 
Coimbra, Portugal; Center for Neurosciences and Cell Biology, University of 
Coimbra, Portugal.
(3)CIEPQPF, Research Center for Chemical Processes Engineering and Forest 
Products, Chemical Engineering Department, Faculty of Sciences and Technology, 
University of Coimbra, Portugal.
(4)Center for Pharmaceutical Studies, Faculty of Pharmacy, University of 
Coimbra, Portugal; Institute for Biomedical Imaging and Life Sciences, 
University of Coimbra, Portugal.

ETHNOPHARMACOLOGICAL RELEVANCE: A variety of plant polyphenols have been 
reported to have anti-inflammatory, frequently associated with erythema, edema, 
hyperplasia, skin photoaging and photocarcinogenesis. Cymbopogon citratus (DC). 
Stapf (Poaceae) is a worldwide known medicinal plant, used in traditional 
medicine in inflammation-related conditions.
AIM OF THE STUDY: In this work, the anti-inflammatory potential of C. citratus 
infusion (CcI) and its polyphenols as topical agents was evaluated in vivo.
MATERIALS AND METHODS: The plant extract was prepared and its fractioning led 
two polyphenol-rich fractions: flavonoids fraction (CcF) and tannins fraction 
(CcT). An oil/water emulsion was developed with each active (CcI, CcF+CcT and 
diclofenac), pH and texture having been evaluated. Release tests were further 
performed using static Franz diffusion cells and all collected samples were 
monitored by HPLC-PDA. In vivo topical anti-inflammatory activity evaluation was 
performed by the carrageenan-induced rat paw edema model.
RESULTS: The texture analysis revealed statistically significant differences for 
all tested parameters to CcF+CcT, supporting its topical application. Release 
experiments lead to the detection of the phenolic compounds from each sample in 
the receptor medium and the six major flavonoids were quantified, by HPLC-PDA: 
carlinoside, isoorientin, cynaroside, luteolin 7-O-neohesperidoside, kurilesin A 
and cassiaoccidentalin B. The CcF+CcT formulation prompted to the higher release 
rate for all these flavonoids. CcI4%, CcI1% and CcF+CcT exhibited an edema 
reduction of 43.18, 29.55 and 59.09%, respectively.
CONCLUSIONS: Our findings highlight that CcI, containing luteolin 
7-O-neohesperidoside, cassiaoccidentalin B, carlinoside, cynaroside and tannins 
have a potential anti-inflammatory topical activity, suggesting their promising 
application in the treatment of skin inflammatory pathologies.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

DOI: 10.1016/j.jep.2015.12.016
PMID: 26702504 [Indexed for MEDLINE]