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BCR-ABL kinase domain mutations, including 2 novel mutations in imatinib resistant Malaysian chronic myeloid leukemia patients-Frequency and clinical outcome

Elias MH, Baba AA, Azlan H, Rosline H, Sim GA, Padmini M, et al.

Leuk. Res., 2014 Apr;38(4):454-9.
PMID: 24456693 DOI: 10.1016/j.leukres.2013.12.025

Discovery of imatinib mesylate (IM) as the targeted BCR-ABL protein tyrosine kinase inhibitor (TKI) has resulted in its use as the frontline therapy for chronic myeloid leukemia (CML) across the world. Although high response rates are observed in CML patients who receive IM treatment, a significant number of patients develop resistance to IM. Resistance to IM in patients has been associated with a heterogeneous array of mechanisms of which point mutations within the ABL tyrosine kinase domain (TKD) are the frequently documented. The types and frequencies of mutations reported in different population studies have shown wide variability. We screened 125 Malaysian CML patients on IM therapy who showed either TKI refractory or resistance to IM to investigate the frequency and pattern of BCR-ABL kinase domain mutations among Malaysian CML patients undergoing IM therapy and to determine the clinical significance. Mutational screening using denaturing high performance liquid chromatography (dHPLC) followed by DNA sequencing was performed on 125 IM resistant Malaysian CML patients. Mutations were detected in 28 patients (22.4%). Fifteen different types of mutations (T315I, E255K, G250E, M351T, F359C, G251E, Y253H, V289F, E355G, N368S, L387M, H369R, A397P, E355A, D276G), including 2 novel mutations were identified, with T315I as the predominant type of mutation. The data generated from clinical and molecular parameters studied were correlated with the survival of CML patients. Patients with Y253H, M351T and E355G TKD mutations showed poorer prognosis compared to those without mutation. Interestingly, when the prognostic impact of the observed mutations was compared inter-individually, E355G and Y253H mutations were associated with more adverse prognosis and shorter survival (P=0.025 and 0.005 respectively) than T315I mutation. Results suggest that apart from those mutations occurring in the three crucial regions (catalytic domain, P-loop and activation-loop), other rare mutations also may have high impact in the development of resistance and adverse prognosis. Presence of mutations in different regions of BCR-ABL TKD leads to different levels of resistance and early detection of emerging mutant clones may help in decision making for alternative treatment. Serial monitoring of BCR-ABL1 transcripts in CML patients allows appropriate selection of CML patients for BCR-ABL1 KD mutation analysis associated with acquired TKI resistance. Identification of these KD mutations is essential in order to direct alternative treatments in such CML patients.

Matched MeSH terms: Catalytic Domain/genetics
An efficient ionic liquid mediated synthesis, cholinesterase inhibitory activity and molecular modeling study of novel piperidone embedded α,β-unsaturated ketones

Kia Y, Osman H, Kumar RS, Murugaiyah V, Basiri A, Khaw KY, et al.

Med Chem, 2014;10(5):512-20.
PMID: 24138113

A series of hitherto unreported piperidone embedded α,β-unsaturated ketones were synthesized efficiently in ionic solvent and evaluated for cholinesterase inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Most of the synthesized compounds displayed good enzyme inhibition; therein compounds 7i and 7f displayed significant activity against AChE with IC50 values of 1.47 and 1.74 µM, respectively. Compound 6g showed the highest BChE inhibitory potency with IC50 value of 3.41 µM, being 5 times more potent than galanthamine. Molecular modeling simulation was performed using AChE and BChE receptors extracted from crystal structure of human AChE and human BChE to determine the amino acid residues involved in the binding interaction of synthesized compounds and their relevant receptors.

Matched MeSH terms: Catalytic Domain
Fulltext Combination of oxyanion Gln114 mutation and medium engineering to influence the enantioselectivity of thermophilic lipase from Geobacillus zalihae

Wahab RA, Basri M, Rahman MB, Rahman RN, Salleh AB, Leow TC

Int J Mol Sci, 2012;13(9):11666-80.
PMID: 23109876 DOI: 10.3390/ijms130911666

The substitution of the oxyanion Q114 with Met and Leu was carried out to investigate the role of Q114 in imparting enantioselectivity on T1 lipase. The mutation improved enantioselectivity in Q114M over the wild-type, while enantioselectivity in Q114L was reduced. The enantioselectivity of the thermophilic lipases, T1, Q114L and Q114M correlated better with log p as compared to the dielectric constant and dipole moment of the solvents. Enzyme activity was good in solvents with log p < 3.5, with the exception of hexane which deviated substantially. Isooctane was found to be the best solvent for the esterification of (R,S)-ibuprofen with oleyl alcohol for lipases Q114M and Q114L, to afford E values of 53.7 and 12.2, respectively. Selectivity of T1 was highest in tetradecane with E value 49.2. Solvents with low log p reduced overall lipase activity and dimethyl sulfoxide (DMSO) completely inhibited the lipases. Ester conversions, however, were still low. Molecular sieves employed as desiccant were found to adversely affect catalysis in the lipase variants, particularly in Q114M. The higher desiccant loading also increased viscosity in the reaction and further reduced the efficiency of the lipase-catalyzed esterifications.

Matched MeSH terms: Catalytic Domain
Fragment-based molecular design of new competitive dengue Den2 Ns2b/Ns3 inhibitors from the components of fingerroot (Boesenbergia rotunda)

Frimayanti N, Zain SM, Lee VS, Wahab HA, Yusof R, Abd Rahman N

In Silico Biol. (Gedrukt), 2011;11(1-2):29-37.
PMID: 22475750 DOI: 10.3233/ISB-2012-0442

Publication year=2011-2012

Matched MeSH terms: Catalytic Domain
Blood-brain barrier permeable anticholinesterase aurones: synthesis, structure-activity relationship, and drug-like properties

Liew KF, Chan KL, Lee CY

Eur J Med Chem, 2015 Apr 13;94:195-210.
PMID: 25768702 DOI: 10.1016/j.ejmech.2015.02.055

A series of novel aurones bearing amine and carbamate functionalities at various positions (rings A and/or B) of the scaffold was synthesized and evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activities. Structure-activity relationship study disclosed several potent submicromolar acetylcholinesterase inhibitors (AChEIs) particularly aurones bearing piperidine and pyrrolidine moieties at ring A or ring B. Bulky groups particularly methoxyls, and carbamate to a lesser extent, at either rings were also prominently featured in these AChEI aurones as exemplified by the trimethoxyaurone 4-3. The active aurones exhibited a lower butyrylcholinesterase inhibition. A 3'-chloroaurone 6-3 originally designed to improve the metabolic stability of the scaffold was the most potent of the series. Molecular docking simulations showed these AChEI aurones to adopt favourable binding modes within the active site gorge of the Torpedo californica AChE (TcAChE) including an unusual chlorine-π interaction by the chlorine of 6-3 to establish additional bondings to hydrophobic residues of TcAChE. Evaluation of the potent aurones for their blood-brain barrier (BBB) permeability and metabolic stability using PAMPA-BBB assay and in vitro rat liver microsomes (RLM) identified 4-3 as an aurone with an optimal combination of high passive BBB permeability and moderate CYP450 metabolic stability. LC-MS identification of a mono-hydroxylated metabolite found in the RLM incubation of 4-3 provided an impetus for further improvement of the compound. Thus, 4-3, discovered within this present series is a promising, drug-like lead for the development of the aurones as potential multipotent agents for Alzheimer's disease.

Matched MeSH terms: Catalytic Domain
Fulltext Carnosine to Combat Novel Coronavirus (nCoV): Molecular Docking and Modeling to Cocrystallized Host Angiotensin-Converting Enzyme 2 (ACE2) and Viral Spike Protein

Saadah LM, Deiab GIA, Al-Balas Q, Basheti IA

Molecules, 2020 Nov 28;25(23).
PMID: 33260592 DOI: 10.3390/molecules25235605

AIMS: Angiotensin-converting enzyme 2 (ACE2) plays an important role in the entry of coronaviruses into host cells. The current paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease (COVID-19) on the basis of molecular docking and modeling to host ACE2 cocrystallized with nCoV spike protein.
METHODS: First, the starting point was ACE2 inhibitors and their structure-activity relationship (SAR). Next, chemical similarity (or diversity) and PubMed searches made it possible to repurpose and assess approved or experimental drugs for COVID-19. Parallel, at all stages, the authors performed bioactivity scoring to assess potential repurposed inhibitors at ACE2. Finally, investigators performed molecular docking and modeling of the identified drug candidate to host ACE2 with nCoV spike protein.
RESULTS: Carnosine emerged as the best-known drug candidate to match ACE2 inhibitor structure. Preliminary docking was more optimal to ACE2 than the known typical angiotensin-converting enzyme 1 (ACE1) inhibitor (enalapril) and quite comparable to known or presumed ACE2 inhibitors. Viral spike protein elements binding to ACE2 were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the protein-protein structure, carnosine bound with higher affinity to two compared to the known ACE2 active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49.
CONCLUSION: Carnosine has promising inhibitory interactions with host ACE2 and nCoV spike protein and hence could offer a potential mitigating effect against the current COVID-19 pandemic.

Matched MeSH terms: Catalytic Domain
Characterization of two novel bacterial type A exo-chitobiose hydrolases having C-terminal 5/12-type carbohydrate-binding modules

Jamek SB, Nyffenegger C, Muschiol J, Holck J, Meyer AS, Mikkelsen JD

Appl Microbiol Biotechnol, 2017 Jun;101(11):4533-4546.
PMID: 28280871 DOI: 10.1007/s00253-017-8198-4

Type A chitinases (EC 3.2.1.14), GH family 18, attack chitin ((1 → 4)-2-acetamido-2-deoxy-β-D-glucan) and chito-oligosaccharides from the reducing end to catalyze release of chitobiose (N,N'-diacetylchitobiose) via hydrolytic cleavage of N-acetyl-β-D-glucosaminide (1 → 4)-β-linkages and are thus "exo-chitobiose hydrolases." In this study, the chitinase type A from Serratia marcescens (SmaChiA) was used as a template for identifying two novel exo-chitobiose hydrolase type A enzymes, FbalChi18A and MvarChi18A, originating from the marine organisms Ferrimonas balearica and Microbulbifer variabilis, respectively. Both FbalChi18A and MvarChi18A were recombinantly expressed in Escherichia coli and were confirmed to exert exo-chitobiose hydrolase activity on chito-oligosaccharides, but differed in temperature and pH activity response profiles. Amino acid sequence comparison of the catalytic β/α barrel domain of each of the new enzymes showed individual differences, but ~69% identity of each to that of SmaChiA and highly conserved active site residues. Superposition of a model substrate on 3D structural models of the catalytic domain of the enzymes corroborated exo-chitobiose hydrolase type A activity for FbalChi18A and MvarChi18A, i.e., substrate attack from the reducing end. A main feature of both of the new enzymes was the presence of C-terminal 5/12 type carbohydrate-binding modules (SmaChiA has no C-terminal carbohydrate binding module). These new enzymes may be useful tools for utilization of chitin as an N-acetylglucosamine donor substrate via chitobiose.

Matched MeSH terms: Catalytic Domain
Synthesis of novel quinoline-based thiadiazole, evaluation of their antileishmanial potential and molecular docking studies

Almandil NB, Taha M, Rahim F, Wadood A, Imran S, Alqahtani MA, et al.

Bioorg Chem, 2019 04;85:109-116.
PMID: 30605884 DOI: 10.1016/j.bioorg.2018.12.025

New series of quinoline-based thiadiazole analogs (1-20) were synthesized, characterized by EI-MS, 1H NMR and 13C NMR. All synthesized compounds were subjected to their antileishmanial potential. Sixteen analogs 1-10, 12, 13, 16, 17, 18 and 19 with IC50 values in the range of 0.04 ± 0.01 to 5.60 ± 0.21 µM showed tremendously potent inhibition as compared to the standard pentamidine with IC50 value 7.02 ± 0.09 µM. Analogs 11, 14, 15 and 20 with IC50 8.20 ± 0.35, 9.20 ± 0.40, 7.20 ± 0.20 and 9.60 ± 0.40 µM respectively showed good inhibition when compared with the standard. Structure-activity relationships have been also established for all compounds. Molecular docking studies were performed to determine the binding interaction of the compounds with the active site target.

Matched MeSH terms: Catalytic Domain
Cyanobacterial aldehyde deformylating oxygenase: Structure, function, and potential in biofuels production

Basri RS, Rahman RNZRA, Kamarudin NHA, Ali MSM

Int J Biol Macromol, 2020 Dec 01;164:3155-3162.
PMID: 32841666 DOI: 10.1016/j.ijbiomac.2020.08.162

The conversion of aldehydes to valuable alkanes via cyanobacterial aldehyde deformylating oxygenase is of great interest. The availability of fossil reserves that keep on decreasing due to human exploitation is worrying, and even more troubling is the combustion emission from the fuel, which contributes to the environmental crisis and health issues. Hence, it is crucial to use a renewable and eco-friendly alternative that yields compound with the closest features as conventional petroleum-based fuel, and that can be used in biofuels production. Cyanobacterial aldehyde deformylating oxygenase (ADO) is a metal-dependent enzyme with an α-helical structure that contains di‑iron at the active site. The substrate enters the active site of every ADO through a hydrophobic channel. This enzyme exhibits catalytic activity toward converting Cn aldehyde to Cn-1 alkane and formate as a co-product. These cyanobacterial enzymes are small and easy to manipulate. Currently, ADOs are broadly studied and engineered for improving their enzymatic activity and substrate specificity for better alkane production. This review provides a summary of recent progress in the study of the structure and function of ADO, structural-based engineering of the enzyme, and highlight its potential in producing biofuels.

Matched MeSH terms: Catalytic Domain
Investigating the binding preferences of small molecule inhibitors of human protein arginine methyltransferase 1 using molecular modelling

Hong W, Li J, Laughton CA, Yap LF, Paterson IC, Wang H

J Mol Graph Model, 2014 Jun;51:193-202.
PMID: 24937176 DOI: 10.1016/j.jmgm.2014.05.010

Protein arginine methyltransferases (PRMTs) catalyse the methylation of arginine residues of target proteins. PRMTs utilise S-adenosyl methionine (SAM) as the methyl group donor, leading to S-adenosyl homocysteine (SAH) and monomethylarginine (mMA). A combination of homology modelling, molecular docking, Active Site Pressurisation, molecular dynamic simulations and MM-PBSA free energy calculations is used to investigate the binding poses of three PRMT1 inhibitors (ligands 1-3), which target both SAM and substrate arginine binding sites by containing a guanidine group joined by short linkers with the SAM derivative. It was assumed initially that the adenine moieties of the inhibitors would bind in sub-site 1 (PHE44, GLU137, VAL136 and GLU108), the guanidine side chain would occupy sub-site 2 (GLU 161, TYR160, TYR156 and TRP302), with the amino acid side chain occupying sub-site 3 (GLU152, ARG62, GLY86 and ASP84; pose 1). However, the SAH homocysteine moiety does not fully occupy sub-site 3, suggesting another binding pose may exist (pose 2), whereby the adenine moiety binds in sub-site 1, the guanidine side chain occupies sub-site 3, and the amino acid side chain occupies sub-site 2. Our results indicate that ligand 1 (pose 1 or 2), ligand 2 (pose 2) and ligand 3 (pose 1) are the predominant binding poses and we demonstrate for the first time that sub-site 3 contains a large space that could be exploited in the future to develop novel inhibitors with higher binding affinities.

Matched MeSH terms: Catalytic Domain
Toluene promotes lid 2 interfacial activation of cold active solvent tolerant lipase from Pseudomonas fluorescens strain AMS8

Yaacob N, Mohamad Ali MS, Salleh AB, Rahman RNZRA, Leow ATC

J Mol Graph Model, 2016 07;68:224-235.
PMID: 27474867 DOI: 10.1016/j.jmgm.2016.07.003

The utilization of cold active lipases in organic solvents proves an excellent approach for chiral synthesis and modification of fats and oil due to the inherent flexibility of lipases under low water conditions. In order to verify whether this lipase can function as a valuable synthetic catalyst, the mechanism concerning activation of the lid and interacting solvent residues in the presence of organic solvent must be well understood. A new alkaline cold-adapted lipase, AMS8, from Pseudomonas fluorescens was studied for its structural adaptation and flexibility prior to its exposure to non-polar, polar aprotic and protic solvents. Solvents such as ethanol, toluene, DMSO and 2-propanol showed to have good interactions with active sites. Asparagine (Asn) and tyrosine (Tyr) were key residues attracted to solvents because they could form hydrogen bonds. Unlike in other solvents, Phe-18, Tyr-236 and Tyr-318 were predicted to have aromatic-aromatic side-chain interactions with toluene. Non-polar solvent also was found to possess highest energy binding compared to polar solvents. Due to this circumstance, the interaction of toluene and AMS8 lipase was primarily based on hydrophobicity and molecular recognition. The molecular dynamic simulation showed that lid 2 (residues 148-167) was very flexible in toluene and Ca(2+). As a result, lid 2 moves away from the catalytic areas, leaving an opening for better substrate accessibility which promotes protein activation. Only a single lid (lid 2) showed the movement following interactions with toluene, although AMS8 lipase displayed double lids. The secondary conformation of AMS8 lipase that was affected by toluene observed a reduction of helical strands and increased coil structure. Overall, this work shows that cold active lipase, AMS8 exhibits distinguish interfacial activation and stability in the presence of polar and non-polar solvents.

Matched MeSH terms: Catalytic Domain
Computational docking, molecular dynamics simulation and subsite structure analysis of a maltogenic amylase from Bacillus lehensis G1 provide insights into substrate and product specificity

Manas NH, Bakar FD, Illias RM

J Mol Graph Model, 2016 06;67:1-13.
PMID: 27155296 DOI: 10.1016/j.jmgm.2016.04.004

Maltogenic amylase (MAG1) from Bacillus lehensis G1 displayed the highest hydrolysis activity on β-cyclodextrin (β-CD) to produce maltose as a main product and exhibited high transglycosylation activity on malto-oligosaccharides with polymerization degree of three and above. These substrate and product specificities of MAG1 were elucidated from structural point of view in this study. A three-dimensional structure of MAG1 was constructed using homology modeling. Docking of β-CD and malto-oligosaccharides was then performed in the MAG1 active site. An aromatic platform in the active site was identified which is responsible in substrate recognition especially in determining the enzyme's preference toward β-CD. Molecular dynamics (MD) simulation showed MAG1 structure is most stable when docked with β-CD and least stable when docked with maltose. The docking analysis and MD simulation showed that the main subsites for substrate stabilization in the active site are -2, -1, +1 and +2. A bulky residue, Trp359 at the +2 subsite was identified to cause steric interference to the bound linear malto-oligosaccharides thus prevented it to occupy subsite +3, which can only be reached by a highly bent glucose molecule such as β-CD. The resulted modes of binding from docking simulation show a good correlation with the experimentally determined hydrolysis pattern. The subsite structure generated from this study led to a possible mode of action that revealed how maltose was mainly produced during hydrolysis. Furthermore, maltose only occupies subsite +1 and +2, therefore could not be hydrolyzed or transglycosylated by the enzyme. This important knowledge has paved the way for a novel structure-based molecular design for modulation of its catalytic activities.

Matched MeSH terms: Catalytic Domain
Synthesis and biological activity of oxadiazole and triazolothiadiazole derivatives as tyrosinase inhibitors

Lam KW, Syahida A, Ul-Haq Z, Abdul Rahman MB, Lajis NH

Bioorg Med Chem Lett, 2010 Jun 15;20(12):3755-9.
PMID: 20493688 DOI: 10.1016/j.bmcl.2010.04.067

A series of 16 oxadiazole and triazolothiadiazole derivatives were designed, synthesized and evaluated as mushroom tyrosinase inhibitors. Five derivatives were found to display high inhibition on the tyrosinase activity ranging from 0.87 to 1.49 microM. Compound 5 exhibited highest tyrosinase inhibitory activity with an IC(50) value of 0.87+/-0.16 microM. The in silico protein-ligand docking using AUTODOCK 4.1 was successfully performed on compound 5 with significant binding energy value of -5.58 kcal/mol. The docking results also showed that the tyrosinase inhibition might be due to the metal chelating effect by the presence of thione functionality in compounds 1-5. Further studies revealed that the presence of hydrophobic group such as cycloamine derivatives played a major role in the inhibition. Piperazine moiety in compound 5 appeared to be involved in an extensive hydrophobic contact and a 2.9A hydrogen bonding with residue Glu 182 in the active site.

Matched MeSH terms: Catalytic Domain
Rational design of bis-indolylmethane-oxadiazole hybrids as inhibitors of thymidine phosphorylase

Taha M, Rashid U, Imran S, Ali M

Bioorg Med Chem, 2018 07 23;26(12):3654-3663.
PMID: 29853339 DOI: 10.1016/j.bmc.2018.05.046

Inhibition of Thymidine phosphorylase (TP) is continuously studied for the design and development of new drugs for the treatment of neoplastic diseases. As a part of our effort to identify TP inhibitors, we performed a structure-based virtual screening (SBVS) of our compound collection. Based on the insights gained from structures of virtual screening hits, a scaffold was designed using 1,3,4-oxadiazole as the basic structural feature and SAR studies were carried out for the optimization of this scaffold. Twenty-five novel bis-indole linked 1,3,4-oxadiazoles (7-31) were designed, synthesized and tested in vitro against E. coli TP (EcTP). Compound 7 emerged as potent TP inhibitor with an IC50 value of 3.50 ± 0.01 μM. Docking studies were carried out using GOLD software on thymidine phosphorylase from human (hTP) and E. coli (EcTP). Various hydrogen bonding, hydrophobic interactions, and π-π stacking were observed between designed molecules and the active site amino acid residues of the studied enzymes.

Matched MeSH terms: Catalytic Domain
Fulltext Novel biphenyl ester derivatives as tyrosinase inhibitors: Synthesis, crystallographic, spectral analysis and molecular docking studies

Kwong HC, Chidan Kumar CS, Mah SH, Chia TS, Quah CK, Loh ZH, et al.

PLoS One, 2017;12(2):e0170117.
PMID: 28241010 DOI: 10.1371/journal.pone.0170117

Biphenyl-based compounds are clinically important for the treatments of hypertension and inflammatory, while many more are under development for pharmaceutical uses. In the present study, a series of 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl benzoates, 2(a-q), and 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl pyridinecarboxylate, 2(r-s) were synthesized by reacting 1-([1,1'-biphenyl]-4-yl)-2-bromoethan-1-one with various carboxylic acids using potassium carbonate in dimethylformamide at ambient temperature. Single-crystal X-ray diffraction studies revealed a more closely packed crystal structure can be produced by introduction of biphenyl moiety. Five of the compounds among the reported series exhibited significant anti-tyrosinase activities, in which 2p, 2r and 2s displayed good inhibitions which are comparable to standard inhibitor kojic acid at concentrations of 100 and 250 μg/mL. The inhibitory effects of these active compounds were further confirmed by computational molecular docking studies and the results revealed the primary binding site is active-site entrance instead of inner copper binding site which acted as the secondary binding site.

Matched MeSH terms: Catalytic Domain
New Hybrid Scaffolds based on Hydrazinyl Thiazole Substituted Coumarin; As Novel Leads of Dual Potential; In Vitro α-Amylase Inhibitory and Antioxidant (DPPH and ABTS Radical Scavenging) Activities

Salar U, Khan KM, Chigurupati S, Syed S, Vijayabalan S, Wadood A, et al.

Med Chem, 2019;15(1):87-101.
PMID: 30179139 DOI: 10.2174/1573406414666180903162243

BACKGROUND: Despite many side effects associated, there are many drugs which are being clinically used for the treatment of type-II diabetes mellitus (DM). In this scenario, there is still need to develop new therapeutic agents with more efficacy and less side effects. By keeping in mind the diverse spectrum of biological potential associated with coumarin and thiazole, a hybrid class based on these two heterocycles was synthesized.
METHOD: Hydrazinyl thiazole substituted coumarins 4-20 were synthesized via two step reaction. First step was the acid catalyzed reaction of 3-formyl/acetyl coumarin derivatives with thiosemicarbazide to form thiosemicarbazone intermediates 1-3, followed by the reaction with different phenacyl bromides to afford products 4-20. All the synthetic analogs 4-20 were characterized by different spectroscopic techniques such as EI-MS, HREI-MS, 1H-NMR and 13C-NMR. Stereochemical assignment of the iminic double bond was carried out by the NOESY experiments. Elemental analysis was found in agreement with the calculated values.
RESULTS: Compounds 4-20 were screened for α-amylase inhibitory activity and showed good activity in the range of IC50 = 1.829 ± 0.102-3.37 ± 0.17 µM as compared to standard acarbose (IC50 = 1.819 ± 0.19 µM). Compounds were also investigated for their DPPH and ABTS radical scavenging activities and displayed good radical scavenging potential. In addition to that molecular modelling study was conducted on all compounds to investigate the interaction details of compounds 4- 20 (ligands) with active site (receptor) of enzyme.
CONCLUSION: The newly identified hybrid class may serve as potential lead candidates for the management of diabetes mellitus.

Matched MeSH terms: Catalytic Domain
Molecular Insight and Mode of Inhibition of α-Glucosidase and α-Amylase by Pahangensin A from Alpinia pahangensis Ridl

Loo KY, Leong KH, Sivasothy Y, Ibrahim H, Awang K

Chem Biodivers, 2019 Jun;16(6):e1900032.
PMID: 30957403 DOI: 10.1002/cbdv.201900032

The inhibition of carbohydrate-hydrolyzing enzymes in human digestive organs is crucial in controlling blood sugar levels, which is important in treating type 2 diabetes. In the current study, pahangensin A (1), a bis-labdanic diterpene characterized previously in the rhizomes of Alpinia pahangensis Ridl., was identified as an active dual inhibitor for α-amylase (IC50 =114.80 μm) and α-glucosidase (IC50 =153.87 μm). This is the first report on the dual α-amylase and α-glucosidase inhibitory activities of a bis-labdanic diterpene. The Lineweaver-Burk plots of compound 1 indicate that it is a mixed-type inhibitor with regard to both enzymes. Based on molecular docking studies, compound 1 docked in a non-active site of both enzymes. The dual inhibitory activity of compound 1 makes it a suitable natural alternative in the treatment of type 2 diabetes.

Matched MeSH terms: Catalytic Domain
Synthesis and in vitro study of benzofuran hydrazone derivatives as novel alpha-amylase inhibitor

Taha M, Shah SAA, Imran S, Afifi M, Chigurupati S, Selvaraj M, et al.

Bioorg Chem, 2017 12;75:78-85.
PMID: 28918064 DOI: 10.1016/j.bioorg.2017.09.002

The α-amylase acts as attractive target to treat type-2 diabetes mellitus. Therefore in discovering a small molecule as α-amylase inhibitor, we have synthesized benzofuran carbohydrazide analogs (1-25), characterized through different spectroscopic techniques such as 1HNMR and EI-MS. All screened analog shows good α-amylase inhibitory potentials with IC50 value ranging between 1.078±0.19 and 2.926±0.05µM when compared with acarbose having IC50=0.62±0.22µM. Only nine analogs among the series such as analogs 3, 5, 7, 8, 10, 12, 21, 23 and 24 exhibit good inhibitory potential with IC50 values 1.644±0.128, 1.078±0.19, 1.245±0.25, 1.843±0.19, 1.350±0.24, 1.629±0.015, 1.353±0.232, 1.359±0.119 and 1.488±0.07µM when compare with standard drug acarbose. All other analogs showed good to moderate α-amylase inhibitory potentials. The SAR study was conducted on the basis of substituent difference at the phenyl ring. The binding interaction between analogs and active site of enzyme was confirmed by docking studies.

Matched MeSH terms: Catalytic Domain
Oxindole based oxadiazole hybrid analogs: Novel α-glucosidase inhibitors

Taha M, Imran S, Rahim F, Wadood A, Khan KM

Bioorg Chem, 2018 02;76:273-280.
PMID: 29223804 DOI: 10.1016/j.bioorg.2017.12.001

Inhibition of α-glucosidase is an effective strategy for controlling post-prandial hyperglycemia in diabetic patients. Beside these α-glucosidase inhibitors has been also used as anti-obesity and anti-viral drugs. Keeping in view the greater importance of α-glucosidase inhibitors here in this study we are presenting oxindole based oxadiazoles hybrid analogs (1-20) synthesis, characterized by different spectroscopic techniques including 1H NMR and EI-MS and their α-glucosidase inhibitory activity. All compounds were found potent inhibitors for the enzyme with IC50 values ranging between 1.25 ± 0.05 and 268.36 ± 4.22 µM when compared with the standard drug acarbose having IC50 value 895.09 ± 2.04 µM. Our study identifies novel series of potent α-glucosidase inhibitors and further investigation on this may led to the lead compounds. A structure activity relationship has been established for all compounds. The interactions of the active compounds and enzyme active site were established with the help of molecular docking studies.

Matched MeSH terms: Catalytic Domain
Fulltext Binding mode analysis of zerumbone to key signal proteins in the tumor necrosis factor pathway

Fatima A, Abdul AB, Abdullah R, Karjiban RA, Lee VS

Int J Mol Sci, 2015 Jan 26;16(2):2747-66.
PMID: 25629232 DOI: 10.3390/ijms16022747

Breast cancer is the second most common cancer among women worldwide. Several signaling pathways have been implicated as causative and progression agents. The tumor necrosis factor (TNF) α protein plays a dual role in promoting and inhibiting cancer depending largely on the pathway initiated by the binding of the protein to its receptor. Zerumbone, an active constituent of Zingiber zerumbet, Smith, is known to act on the tumor necrosis factor pathway upregulating tumour necrosis factor related apoptosis inducing ligand (TRAIL) death receptors and inducing apoptosis in cancer cells. Zerumbone is a sesquiterpene that is able to penetrate into the hydrophobic pockets of proteins to exert its inhibiting activity with several proteins. We found a good binding with the tumor necrosis factor, kinase κB (IKKβ) and the Nuclear factor κB (NF-κB) component proteins along the TNF pathway. Our results suggest that zerumbone can exert its apoptotic activities by inhibiting the cytoplasmic proteins. It inhibits the IKKβ kinase that activates the NF-κB and also binds to the NF-κB complex in the TNF pathway. Blocking both proteins can lead to inhibition of cell proliferating proteins to be downregulated and possibly ultimate induction of apoptosis.

Matched MeSH terms: Catalytic Domain

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