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Target-Based Virtua...
Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity
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- Uddin, Amad (author)
- Jamia Millia Islamia, Med Chem Lab, Dept Biosci, New Delhi, India.;Jawaharlal Nehru Univ, Special Ctr Mol Med, New Delhi, India.
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- Gupta, Sonal (author)
- Jawaharlal Nehru Univ, Special Ctr Mol Med, New Delhi, India.
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- Mohammad, Taj (author)
- Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi, India.
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- Shahi, Diksha (author)
- Jawaharlal Nehru Univ, Special Ctr Mol Med, New Delhi, India.
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- Hussain, Afzal (author)
- King Saud Univ, Coll Pharm, Dept Pharmacognosy, Riyadh, Saudi Arabia.
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- Alajmi, Mohamed F. (author)
- King Saud Univ, Coll Pharm, Dept Pharmacognosy, Riyadh, Saudi Arabia.
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- El-Seedi, Hesham R. (author)
- Uppsala universitet,Farmakognosi
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- Hassan, Imtaiyaz (author)
- Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi, India.
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- Singh, Shailja (author)
- Jawaharlal Nehru Univ, Special Ctr Mol Med, New Delhi, India.
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- Abid, Mohammad (author)
- Jamia Millia Islamia, Med Chem Lab, Dept Biosci, New Delhi, India.
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Jamia Millia Islamia, Med Chem Lab, Dept Biosci, New Delhi, India;Jawaharlal Nehru Univ, Special Ctr Mol Med, New Delhi, India. Jawaharlal Nehru Univ, Special Ctr Mol Med, New Delhi, India. (creator_code:org_t)
- 2022-04-06
- 2022
- English.
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In: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 13
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https://uu.diva-port... (primary) (Raw object)
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Abstract
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- We employed a comprehensive approach of target-based virtual high-throughput screening to find potential hits from the ZINC database of natural compounds against cysteine proteases falcipain-2 and falcipain-3 (FP2 and FP3). Molecular docking studies showed the initial hits showing high binding affinity and specificity toward FP2 were selected. Furthermore, the enzyme inhibition and surface plasmon resonance assays were performed which resulted in a compound ZINC12900664 (ST72) with potent inhibitory effects on purified FP2. ST72 exhibited strong growth inhibition of chloroquine-sensitive (3D7; EC50 = 2.8 µM) and chloroquine-resistant (RKL-9; EC50 = 6.7 µM) strains of Plasmodium falciparum. Stage-specific inhibition assays revealed a delayed and growth defect during parasite growth and development in parasites treated with ST72. Furthermore, ST72 significantly reduced parasite load and increased host survival in a murine model infected with Plasmodium berghei ANKA. No Evans blue staining in ST72 treatment indicated that ST72 mediated protection of blood–brain barrier integrity in mice infected with P. berghei. ST72 did not show any significant hemolysis or cytotoxicity against human HepG2 cells suggesting a good safety profile. Importantly, ST72 with CQ resulted in improved growth inhibitory activity than individual drugs in both in vitro and in vivo studies.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- natural compounds
- virtual screening
- malaria
- in vivo
- in vitro
- falcipain-2 inhibition
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Uddin, Amad
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Gupta, Sonal
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Mohammad, Taj
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Shahi, Diksha
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Hussain, Afzal
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Alajmi, Mohamed ...
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show more...
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El-Seedi, Hesham ...
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Hassan, Imtaiyaz
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Singh, Shailja
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Abid, Mohammad
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
- Articles in the publication
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Frontiers in Pha ...
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Uppsala University