Drug repurposing based novel anti-leishmanial drug screening using <i>in-silico</i> and <i>in-vitro</i> approaches

Rai, Praveen; Arya, Hemant; Saha, Satabdi; Kumar, Diwakar; Bhatt, Tarun Kumar

doi:10.1080/07391102.2021.1950574

Cited by 7 publications

(4 citation statements)

References 42 publications

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“…We chose 8630 approved drugs from various regulatory agencies and their potential to be repurposed against VL in this study. We have performed molecular docking, Molecular Dynamics (MD) simulation, molecular mechanics generalized born surface area (MMGBSA) binding free energy calculations, and Density functional theory (DFT) calculations for chemical reactivity 25–27 …”

Section: Introductionmentioning

confidence: 99%

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Drug repositioning to discover novel ornithine decarboxylase inhibitors against visceral leishmaniasis

Sheikh

Ansari²,

Hassan

et al. 2023

J of Molecular Recognition

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Visceral leishmaniasis (VL) is caused by Leishmania donovani (Ld), and most cases occur in Brazil, East Africa, and India. The treatment for VL is limited and has many adverse effects. The development of safer and more efficacious drugs is urgently needed. Drug repurposing is one of the best processes to repurpose existing drugs. Ornithine decarboxylase (ODC) is an important target against L. donovani in the polyamine biosynthesis pathway. In this study, we have modeled the 3D structure of ODC and performed high‐throughput virtual screening of 8630 ZINC database ligands against Leishmania donovani ornithine decarboxylase (Ld ODC), selecting 45 ligands based on their high binding score. It is further validated through molecular docking simulation and the selection of the top two lead molecules (ceftaroline fosamil and rimegepant) for Molecular Dynamics (MD) simulation, Density functional theory (DFT), and molecular mechanics generalized born surface area (MMGBSA) analysis. The results showed that the binding affinities of ceftaroline fosamil, and rimegepant are, respectively, −10.719 and 10.159 kcal/mol. The docking complexes of the two lead compounds, ceftaroline fosamil, and rimegepant, with the target ODC, were found stable during molecular dynamics simulations. Furthermore, the analysis of MMGBSA revealed that these compounds had a high binding free energy. The DFT analysis showed that the top lead molecules were more reactive than the standard drug (pentamidine). In‐silico findings demonstrated that ceftaroline fosamil, and rimegepant might be recognized as potent antagonists against ODC for the treatment of VL.

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Section: Introductionmentioning

confidence: 99%

“…We have performed molecular docking, Molecular Dynamics (MD) simulation, molecular mechanics generalized born surface area (MMGBSA) binding free energy calculations, and Density functional theory (DFT) calculations for chemical reactivity. [25][26][27] 2 | MATERIALS AND METHODS…”

mentioning

confidence: 99%

Drug repositioning to discover novel ornithine decarboxylase inhibitors against visceral leishmaniasis

Sheikh

Ansari²,

Hassan

et al. 2023

J of Molecular Recognition

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“…The most common methods rely on fluorometric, luminescence or colorimetric readouts to measure parasites viability/growth in microplate readers, which are available in many laboratories. Trypanosomatids viability has been mainly assessed by measuring parasites ATP 28 , 29 , 30 , 31 content and/or by measuring the metabolic reduction of redox probes, such as tetrazolium salts (MTT/XTT/MTS) 32 , 33 , 34 and resazurin. 35 , 36 , 37 The number of parasites has also been indirectly obtained by SYBR Green, 38 , 39 a fluorescent nuclear probe.…”

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confidence: 99%

“… 54 Special attention should also be paid to hits coming from enzyme reporter-based assays since, theoretically, compounds may interfere with enzyme activity (or its substrate) and vice-versa, generating spurious results. 44 , 53 , 54 Moreover, many assays were developed to test compounds against promastigotes 12 , 30 , 32 , 33 , 55 and axenic amastigotes (i.e., amastigotes that are growth in culture media that simulate intracellular conditions) 29 , 53 , 56 evolutionary forms. Though promastigotes are easy to handle and can be obtained in large amounts, which is desirable for HTS campaigns, they represent the vector-transmitted form of the parasite life cycle which is not directly involved in disease development.…”

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confidence: 99%

Past and future of trypanosomatids high-throughput phenotypic screening

Dantas

Torres-Santos

Silva

2022

Mem. Inst. Oswaldo Cruz

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Diseases caused by trypanosomatid parasites affect millions of people mainly living in developing countries. Novel drugs are highly needed since there are no vaccines and available treatment has several limitations, such as resistance, low efficacy, and high toxicity. The drug discovery process is often analogous to finding a needle in the haystack. In the last decades a so-called rational drug design paradigm, heavily dependent on computational approaches, has promised to deliver new drugs in a more cost-effective way. Paradoxically however, the mainstay of these computational methods is data-driven, meaning they need activity data for new compounds to be generated and available in databases. Therefore, high-throughput screening (HTS) of compounds still is a much-needed exercise in drug discovery to fuel other rational approaches. In trypanosomatids, due to the scarcity of validated molecular targets and biological complexity of these parasites, phenotypic screening has become an essential tool for the discovery of new bioactive compounds. In this article we discuss the perspectives of phenotypic HTS for trypanosomatid drug discovery with emphasis on the role of image-based, high-content methods. We also propose an ideal cascade of assays for the identification of new drug candidates for clinical development using leishmaniasis as an example.

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Target-Based Rational Improvement Strategies and Pitfalls in Leishmania Drug Discovery

Gupta,

Goicoechea,

Vance

et al. 2023

Natural Product Based Drug Discovery Against Human Parasites

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Drug repurposing based novel anti-leishmanial drug screening using in-silico and in-vitro approaches

Cited by 7 publications

References 42 publications

Drug repositioning to discover novel ornithine decarboxylase inhibitors against visceral leishmaniasis

Drug repositioning to discover novel ornithine decarboxylase inhibitors against visceral leishmaniasis

Past and future of trypanosomatids high-throughput phenotypic screening

Target-Based Rational Improvement Strategies and Pitfalls in Leishmania Drug Discovery

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