Establishment of correlation between in-silico and in-vitro test analysis against Leishmania HGPRT to inhibitors

Ansari, Yousuf; Equbal, Asif; Dikhit, Manas Ranjan; Mansuri, Rani; Rana, Sindhuprava; Ali, Vahab; Sahoo, Ganesh Chandra; Das, Pradeep

doi:10.1016/j.ijbiomac.2015.11.051

Cited by 34 publications

(17 citation statements)

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“…To further confirm the docking outcome, the binding free energies of these selected representatives were calculated that elucidated their favorable binding with LdAPx. Use of computational software such as Discovery Studio, Schrödinger, FlexX, etc., is a rational approach to drug discovery to find inhibitors for leishmaniasis or other diseases (16,17).…”

Section: Amphotericin B Drug Resistance In Leishmania Donovanimentioning

confidence: 99%

“…Many people have followed this methodology for finding inhibitors against Leishmania donovani using Discovery Studio, Schrödinger, FlexX, etc. (16,17).The major objectives of the present work were to obtain molecular insight into the structure of Leishmania donovani APx (LdAPx) and to identify a structure-based inhibitor that can inhibit LdAPx and may be helpful in developing newer therapeutics.…”

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confidence: 99%

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In Vitro Evaluation of Antileishmanial Activity of Computationally Screened Compounds against Ascorbate Peroxidase To Combat Amphotericin B Drug Resistance

Mansuri

Kumar

Rana

et al. 2017

Antimicrob Agents Chemother

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In visceral leishmaniasis (VL), the host macrophages generate oxidative stress to destroy the pathogen, while Leishmania combats the harmful effect of radicals by redox homeostasis through its unique trypanothione cascade. Leishmania donovani ascorbate peroxidase (LdAPx) is a redox enzyme that regulates the trypanothione cascade and detoxifies the effect of H 2 O 2 . The absence of an LdAPx homologue in humans makes it an excellent drug target. In this study, the homology model of LdAPx was built, including heme, and diverse compounds were prefiltered (PAINS, ADMET, and Lipinski's rule of five) and thereafter screened against the LdAPx model. Compounds having good affinity in terms of the Glide XP (extra precision) score were clustered to select diverse compounds for experimental validation. A total of 26 cluster representatives were procured and tested on promastigote culture, yielding 12 compounds with good antileishmanial activity. Out of them, six compounds were safer on the BALB/c peritoneal macrophages and were also effective against disease-causing intracellular amastigotes. Three out of six compounds inhibited recombinant LdAPx in a noncompetitive manner and also demonstrated partial reversion of the resistance property in an amphotericin B (AmB)-resistant strain, which may be due to an increased level of reactive oxygen species (ROS) and decrease of glutathione (GSH) content. However, inhibition of LdAPx in resistant parasites enhanced annexin V staining and activation of metacaspase-like protease activity, which may help in DNA fragmentation and apoptosis-like cell death. Thus, the present study will help in the search for specific hits and templates of potential therapeutic interest and therefore may facilitate the development of new drugs for combination therapy against VL.KEYWORDS ascorbate peroxidase, phylogenetic analysis, virtual screening and docking, apoptosis, inhibitors, leishmania, enzymatic assay V isceral leishmaniasis (VL) is one of the fatal neglected parasitic diseases and is caused by the flagellated protozoan parasite of the genus Leishmania and family Trypanosomatidae (1). The promastigote forms are transmitted to the host blood through the bite of phlebotomine sand flies (vector) and are differentiated into amastigotes in macrophages, resulting in hepatosplenomegaly (2). According to a WHO report from 2015, approximately 30,000 annual deaths and over 1.3 million new cases were estimated. The countries most affected by VL were noted as Bangladesh, Brazil,

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Section: Amphotericin B Drug Resistance In Leishmania Donovanimentioning

confidence: 99%

mentioning

confidence: 99%

In Vitro Evaluation of Antileishmanial Activity of Computationally Screened Compounds against Ascorbate Peroxidase To Combat Amphotericin B Drug Resistance

Mansuri

Kumar

Rana

et al. 2017

Antimicrob Agents Chemother

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“…Leishmania is a genus of trypanosomes that are responsible for Leishmaniasis disease [40]. Kaur et al [41] showed that 70% ethanolic extract of Moringa oleifera roots exhibit antileishmanial activity with IC 50 values of 83 µg/ml and the methanolic extract of leaves showed antileishmanial activity with IC 50 values of 47.5 µg/ml.…”

Section: Antiparasitic Activity Of Moringa Oleiferamentioning

confidence: 99%

Mini Review on Antimicrobial Activity and Bioactive Compounds of Moringa oleifera

Wang¹,

Chen²,

Wu³

2016

Med chem (Los Angeles)

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Moringa oleifera is a kind of woody tree traditionally used as a nutritional source and as a medicinal plant. It grows wild in the tropical and subtropical areas of Asia, Africa and the Middle East. In China, Moringa oleifera trees are planted at a large scale in Yunnan, Guangdong and Guangxi Provinces. As a nutritional and medicinal plant, Moringa oleifera is a rich source of bioactive compounds with diverse pharmacological activities. It has been widely used in the treatment of certain diseases as a traditional medicinal herb. Antimicrobial activity is the most studied property of Moringa oleifera. Many studies have shown that the leaf, flower, bark, root, seed, and nearly all types of Moringa oleifera tissues exhibit antimicrobial activity including antibacterial, antifungal, antiviral and antiparasitic activity. This review describes progress on research conducted to understand the antimicrobial activity and related bioactive properties of Moringa oleifera compounds, and discusses the potential use of Moringa oleifera in the control of pathogenic microbes.

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“…L. donovani lacks the machinery for the synthesis of purines competing with the hosts for salvaging the required purines (Boitz et al, 2012). Incapability of these organisms to synthesize the purines de novo has led to their dependence on the salvaging of the purines from their hosts rendering the "purine salvage" pathway essential for its survival Ansari et al, 2016). Hence, the pathway has served has a backbone towards the maintenance of purine amounts in the parasitic pool of nutrients (Marr et al, 1978;Looker et al, 1983;De Koning et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

In silico Metabolic Pathway Analysis Identifying Target Against Leishmaniasis – A Kinetic Modeling Approach

Bora

Jha

2020

Front. Genet.

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The protozoan Leishmania donovani, from trypanosomatids family is a deadly human pathogen responsible for causing Visceral Leishmaniasis. Unavailability of proper treatment in the developing countries has served as a major threat to the people. The absence of vaccines has made treatment possibilities to rely solely over chemotherapy. Also, reduced drug efficacy due to emerging resistant strains magnifies the threat. Despite years of formulations for an effective drug therapy, complexity of the disease is also unfortunately increasing. Absence of potential drug targets has worsened the scenario. Therefore exploring new therapeutic approach is a priority for the scientific community to combat the disease. One of the most reliable ways to alter the adversities of the infection is finding new biological targets for designing potential drugs. An era of computational biology allows identifying targets, assisting experimental studies. It includes sorting the parasite's metabolic pathways that pins out proteins essential for its survival. We have directed our study towards a computational methodology for determining targets against L. donovani from the "purine salvage" pathway. This is a mainstay pathway towards the maintenance of purine amounts in the parasitic pool of nutrients proving to be mandatory for its survival. This study represents an integration of metabolic pathway and Protein-Protein Interactions analysis. It consists of incorporating the available experimental data to the theoretical methods with a prospective to develop a kinetic model of Purine salvage pathway. Simulation data revealed the time course mechanism of the enzymes involved in the synthesis of the metabolites. Modeling of the metabolic pathway helped in marking of crucial enzymes. Additionally, the PPI analysis of the pathway assisted in building a static interaction network for the proteins. Topological analysis of the PPI network through centrality measures (MCC and Closeness) detected targets found common with Dynamic Modeling. Therefore our analysis reveals the enzymes ADSL (Adenylosuccinate lyase) and IMPDH (Inosine-5monophosphate dehydrogenase) to be important having a central role in the modeled network based on PPI and kinetic modeling techniques. Further the available three Frontiers in Genetics | www.frontiersin.org 1 March 2020 | Volume 11 | Article 179Bora and Jha Target Identification in L. donovani dimensional structure of the enzyme "ADSL" aided towards the search for potential inhibitors against the protein. Hence, the study presented the significance of integrating methods to identify key proteins which might be putative targets against the treatment of Visceral Leishmaniasis and their potential inhibitors.

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Establishment of correlation between in-silico and in-vitro test analysis against Leishmania HGPRT to inhibitors

Cited by 34 publications

References 65 publications

In Vitro Evaluation of Antileishmanial Activity of Computationally Screened Compounds against Ascorbate Peroxidase To Combat Amphotericin B Drug Resistance

In Vitro Evaluation of Antileishmanial Activity of Computationally Screened Compounds against Ascorbate Peroxidase To Combat Amphotericin B Drug Resistance

Mini Review on Antimicrobial Activity and Bioactive Compounds of Moringa oleifera

In silico Metabolic Pathway Analysis Identifying Target Against Leishmaniasis – A Kinetic Modeling Approach

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