scholarly journals Identification of Leishmania donovani Topoisomerase 1 inhibitors via intuitive scaffold hopping and bioisosteric modification of known Top 1 inhibitors

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Rajinikanth Mamidala ◽  
Papiya Majumdar ◽  
Kunal Kumar Jha ◽  
Chandramohan Bathula ◽  
Rahul Agarwal ◽  
...  
Keyword(s):  
Binding Sites ◽  
Leishmania Donovani ◽  
Scaffold Hopping ◽  
Cos7 Cell ◽  
Single Digit ◽  
Docking Analysis ◽  
Dna Relaxation ◽  
Topoisomerase 1 ◽  
Inhibition Experiment ◽  
Molecular Library

Abstract A library of arylidenefuropyridinediones was discovered as potent inhibitors of Leishmania donovani Topoisomerase 1 (LdTop1) where the active molecules displayed considerable inhibition with single digit micromolar EC50 values. This molecular library was designed via intuitive scaffold hopping and bioisosteric modification of known topoisomerase 1 inhibitors such as camptothecin, edotecarin and etc. The design was rationalized by molecular docking analysis of the compound prototype with human topoisomerase 1 (HTop1) and Leishmania donovani topoisomerase 1(LdTop1). The most active compound 4 displayed no cytotoxicity against normal mammalian COS7 cell line (~100 fold less inhibition at the EC50). Similar to camptothecin, 4 interacted with free LdTop1 as observed in the preincubation DNA relaxation inhibition experiment. It also displayed anti-protozoal activity against Leishmania donovani promastigote. Crystal structure investigation of 4 and its molecular modelling with LdTop1 revealed putative binding sites in the enzyme that could be harnessed to generate molecules with better potency.

scholarly journals Erratum: Corrigendum: Identification of Leishmania donovani Topoisomerase 1 inhibitors via intuitive scaffold hopping and bioisosteric modification of known Top 1 inhibitors

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Rajinikanth Mamidala ◽  
Papiya Majumdar ◽  
Kunal Kumar Jha ◽  
Chandramohan Bathula ◽  
Rahul Agarwal ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Scaffold Hopping ◽  
Topoisomerase 1

scholarly journals Lignin Nanoparticles Deliver Novel Thymine Biomimetic Photo-Adducts with Antimelanoma Activity

2022 ◽  
Vol 23 (2) ◽  
pp. 915
Author(s):  
Sofia Gabellone ◽  
Davide Piccinino ◽  
Silvia Filippi ◽  
Tiziana Castrignanò ◽  
Claudio Zippilli ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Molecular Docking ◽  
Controlled Release ◽  
Selectivity Index ◽  
Docking Analysis ◽  
Topoisomerase 1 ◽  
Thymine Dimers ◽  
Repair Pathways ◽  
Dna Complex ◽  
Molecular Docking Analysis

We report here the synthesis of novel thymine biomimetic photo-adducts bearing an alkane spacer between nucleobases and characterized by antimelanoma activity against two mutated cancer cell lines overexpressing human Topoisomerase 1 (TOP1), namely SKMEL28 and RPMI7951. Among them, Dewar Valence photo-adducts showed a selectivity index higher than the corresponding pyrimidine-(6-4)-pyrimidone and cyclobutane counterpart and were characterized by the highest affinity towards TOP1/DNA complex as evaluated by molecular docking analysis. The antimelanoma activity of novel photo-adducts was retained after loading into UV photo-protective lignin nanoparticles as stabilizing agent and efficient drug delivery system. Overall, these results support a combined antimelanoma and UV sunscreen strategy involving the use of photo-protective lignin nanoparticles for the controlled release of thymine dimers on the skin followed by their sacrificial transformation into photo-adducts and successive inhibition of melanoma and alert of cellular UV machinery repair pathways.

scholarly journals Molecular docking analysis of an isoflavone derivative with the phosphatase 1 protein from Leishmania donovani

2020 ◽  
Vol 16 (11) ◽  
pp. 942-948
Author(s):  
Rahila Qureshi ◽  
Keyword(s):  
Molecular Docking ◽  
Side Effects ◽  
Mortality Rate ◽  
Leishmania Donovani ◽  
Neglected Diseases ◽  
High Morbidity ◽  
Pentanoic Acid ◽  
Docking Analysis ◽  
Parasite Survival ◽  
Molecular Docking Analysis

Leishmaniasis is one of the most neglected diseases with high morbidity and mortality rate. Severe side effects with existing drug and lack of proper vaccine encouraged us to design alternative models to combat the disease. We showed that PP1 of Leishmania donovani mediates immunomodulation in host macrophages needed for parasite survival. Therefore, it is of interest to report the molecular docking analysis of 512 isoflavone derivatives with the phosphatase 1 protein from Leishmania donovani to highlight compound 362 (5-hydroxy-5-{9-[2-methoxy-2-(2-methylfuran-3-yl) ethyl]-1H,3H,4H,10bH-pyrano[4,3-c]chromen-3-yl}pentanoic acid) having good binding features and acceptable ADMET properties for further consideration.

scholarly journals INSILICO STUDIES OF OXIME PRODRUG OF GLICLAZIDE AGAINST SULPHONYLUREA RECEPTORS (SUR 1)

2017 ◽  
Vol 9 (4) ◽  
pp. 100
Author(s):  
Surendran Vijayaraj ◽  
Kannekanti Chaithanya Veena
Keyword(s):  
Binding Sites ◽  
Pancreatic Beta Cells ◽  
Molecular Targets ◽  
Docking Studies ◽  
Docking Analysis ◽  
Potential Binding ◽  
In Silico Study ◽  
Molecular Docking Analysis ◽  
Autodock 4.2

Objective: Objective of the study is to perform a molecular docking analysis of novel oxime prodrug of gliclazide against SUR1 receptor.Methods: Sulfonylurea receptors (SUR) are membrane proteins which are the molecular targets of the sulfonylurea class of anti-diabetic drugs whose mechanism of action is to promote insulin release from pancreatic beta cells. Oxime prodrug of gliclazide a better soluble derivative of gliclazide is used for enhancement of bioavailability of gliclazide. Autodock 4.2 software was used for docking studies. Ligand 2D structures were drawn using ChemDraw Ultra 7.0. Binding sites, docking poses and interactions of the ligand with SUR1 receptors were studied by pymol software.Results: The docking studies suggest that potential binding sites of oxime prodrug of gliclazide exhibiting all the major interactions such as hydrogen bonding, hydrophobic interaction and electrostatic interaction with GLU43, LEU11, LEU 40, ILE17 GLU 68, GLN72 residues of SUR1. The binding energy of complexes are also found to be minimal forming stable complexes.Conclusion: In silico study of oxime prodrug of gliclazide conforms, the binding of oxime prodrug of glicalzide with SUR1 receptors which effectively controls the release insulin to regulate plasma glucose concentrations. Hence, the oxime prodrug of gliclazide could be a potent anti-diabetic target molecule which may be worth for further in vitro and in vivostudies. 

scholarly journals Bioactivity of Spongian Diterpenoid Scaffolds from the Antarctic Sponge Dendrilla antarctica

Marine Drugs ◽  
2020 ◽  
Vol 18 (6) ◽  
pp. 327 ◽  
Author(s):  
Alexandre Bory ◽  
Andrew J. Shilling ◽  
Jessie Allen ◽  
Ala Azhari ◽  
Alison Roth ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Natural Products ◽  
Leishmania Donovani ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Chemical Library ◽  
Single Digit ◽  
Liver Stage ◽  
New Compounds ◽  
The Antarctic ◽  
Small Chemical

The Antarctic sponge Dendrilla antarctica is rich in defensive terpenoids with promising antimicrobial potential. Investigation of this demosponge has resulted in the generation of a small chemical library containing diterpenoid secondary metabolites with bioactivity in an infectious disease screening campaign focused on Leishmania donovani, Plasmodium falciparum, and methicillin-resistant Staphylococcus aureus (MRSA) biofilm. In total, eleven natural products were isolated, including three new compounds designated dendrillins B–D (10–12). Chemical modification of abundant natural products led to three semisynthetic derivatives (13–15), which were also screened. Several compounds showed potency against the leishmaniasis parasite, with the natural products tetrahydroaplysulphurin-1 (4) and dendrillin B (10), as well as the semisynthetic triol 15, displaying single-digit micromolar activity and low mammalian cytotoxicity. Triol 15 displayed the best profile against the liver-stage malaria parasites, while membranolide (5) and dendrillin C (11) were strong hits against MRSA biofilm cultures.

Suramin could block the activity of Arabinono-1, 4-lactone oxidase enzyme from Leishmania donovani: structure-based screening and molecular dynamics analyses

2019 ◽  
Vol 114 (3) ◽  
pp. 162-172 ◽  
Author(s):  
Keivan Adinehbeigi ◽  
Minoo Shaddel ◽  
Saeed Khalili ◽  
Alireza Zakeri
Keyword(s):  
Active Sites ◽  
Leishmania Donovani ◽  
3D Structure ◽  
Current Treatment ◽  
Model Assessment ◽  
Docking Analysis ◽  
Oxidase Enzyme ◽  
Inhibitory Molecules ◽  
Dynamics Analyses

Abstract Background Leishmania donovani, a parasitic protozoan causing visceral leishmaniasis, can lead to a dangerous and often fatal disease in humans. Current treatment for leishmaniasis may have severe side effects, low efficacy and high cost, hence an immediate need for new efficient drugs is essential. Arabinono-1, 4-lactone oxidase enzyme from Leishmania donovani (LdALO), which catalyzes the last step of the ascorbate biosynthesis pathway, has been considered as a potential target for antileishmanial drugs design. Methods The current study was performed with an in silico approach to predict novel inhibitory molecules against the LdALO enzyme. Various modeling and refinement processes were employed to obtain a reliable 3D structure. Results The best LdALO model with the highest qualitative model energy analysis score was predicted by the Robetta server and subsequently refined by 3D refine and ModLoop servers. The high quality of the final LdALO model was confirmed using model assessment software. Based on docking analysis results, we predicted 10 inhibitory molecules of a US Food and Drug Administration-approved library, with appropriate criteria regarding energy binding and interaction with the main functionally active sites of LdALO, indicating that they could be significant targets for further drug design investigations against L. donovani. Conclusion Suramin is used to treat the first stage of African sleeping sickness and its mechanism of action is unknown. Our results showed that suramin was the best-predicted inhibitor compound for LdALO enzyme activity.

scholarly journals Identification of Suitable Agents against Adenine Phosphoribosyl Transferase for the Management of Leishmaniasis: Synthesis, Characterization and Computational Studies

2021 ◽  
Vol 12 (6) ◽  
pp. 7503-7522
Keyword(s):  
Leishmania Donovani ◽  
Antileishmanial Activity ◽  
Standard Drug ◽  
Docking Analysis ◽  
Equivalent Number ◽  
In Silico Admet ◽  
Drug Score ◽  
Diphenyl Tetrazolium Bromide ◽  
Genus Leishmania

A leishmaniasis is a group of diseases attributable to protozoan parasites of the genus Leishmania. It is a potential disease mostly occurring in developing nations. Various quinoline substituted derivatives (11a-f, 12a-f, and 13a-f) were synthesized by refluxing amino quinolines with an equivalent number of different alkylaminoethyl chlorides and evaluated for their in vitro antileishmanial activity against promastigotes forms of Leishmania donovani by using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] reduction assay. Compounds 11f (IC50 = 13.61μg/mL), 12f (IC50 = 11.92 μg/mL) and 13f (IC50 =10.41 μg/mL) have shown significant antileishmanial activity when compared with standard sitamaquine (IC50= 10.09 μg/mL). Furthermore, the molecular docking analysis targeting adenine phosphoribosyltransferase of Leishmania donovani exhibits significant binding interactions. In silico, ADMET predictions revealed that these compounds, i.e., 11f, 12f, and 13f, demonstrated good absorption as well as solubility characteristics with good drug-likeness and drug score values compared to the standard drug.

scholarly journals Identification of the Enzyme Responsible forN-Acetylation of Norfloxacin by Microbacterium sp. Strain 4N2-2

2012 ◽  
Vol 79 (1) ◽  
pp. 314-321 ◽  
Author(s):  
Dae-Wi Kim ◽  
Jinhui Feng ◽  
Huizhong Chen ◽  
Ohgew Kweon ◽  
Yuan Gao ◽  
...  
Keyword(s):  
Binding Sites ◽  
Treatment Plant ◽  
Biochemical Properties ◽  
Fluoroquinolone Resistance ◽  
Optimal Conditions ◽  
Acetyl Coenzyme A ◽  
Docking Analysis ◽  
Content Type ◽  
Potential Binding ◽  
Environmental Bacteria

ABSTRACTMicrobacteriumsp. 4N2-2, isolated from a wastewater treatment plant, converts the antibacterial fluoroquinolone norfloxacin toN-acetylnorfloxacin and three other metabolites. BecauseN-acetylation results in loss of antibacterial activity, identification of the enzyme responsible is important for understanding fluoroquinolone resistance. The enzyme was identified as glutamine synthetase (GS);N-acetylnorfloxacin was produced only under conditions associated with GS expression. The GS gene (glnA) was cloned, and the protein (53 kDa) was heterologously expressed and isolated. Optimal conditions and biochemical properties (KmandVmax) of purified GS were characterized; the purified enzyme was inhibited by Mn2+, Mg2+, ATP, and ADP. The contribution of GS to norfloxacin resistance was shown by using a norfloxacin-sensitiveEscherichia colistrain carryingglnAderived fromMicrobacteriumsp. 4N2-2. The GS ofMicrobacteriumsp. 4N2-2 was shown to act as anN-acetyltransferase for norfloxacin, which produced low-level norfloxacin resistance. Structural and docking analysis identified potential binding sites for norfloxacin at the ADP binding site and for acetyl coenzyme A (acetyl-CoA) at a cleft in GS. The results suggest that environmental bacteria whose enzymes modify fluoroquinolones may be able to survive in the presence of low fluoroquinolone concentrations.

scholarly journals Par-4 Binds to Topoisomerase 1 and Attenuates Its DNA Relaxation Activity

2008 ◽  
Vol 68 (15) ◽  
pp. 6190-6198 ◽  
Author(s):  
Anindya Goswami ◽  
Shirley Qiu ◽  
Thomas S. Dexheimer ◽  
Padhma Ranganathan ◽  
Ravshan Burikhanov ◽  
...  
Keyword(s):  
Relaxation Activity ◽  
Dna Relaxation ◽  
Topoisomerase 1
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