Inverse Virtual Screening allows the discovery of the biological activity of natural compounds

Background: P-21 activating kinase 4 (PAK4) is implicated in poor prognosis of many cancers, especially in the progression of Triple Negative Breast Cancer (TNBC). The present study was aimed at designing some potential drug candidates as PAK4 inhibitors for breast cancer therapy. Objective: This study aimed to finding novel inhibitors of PAK4 from natural compounds using computational approach. Methods: An e-pharmacophore model was developed from docked PAK4-coligand complex and used to screen over a thousand natural compounds downloaded from BIOFACQUIM and NPASS databases to match a minimum of 5 sites for selected (ADDDHRR) hypothesis. The robustness of the virtual screening method was accessed by well-established methods including EF, ROC, BEDROC, AUAC, and the RIE. Compounds with fitness score greater than one were filtered by applying molecular docking (HTVS, SP, XP and Induced fit docking) and ADME prediction. Using Machine learningbased approach QSAR model was generated using Automated QSAR. The computed top model kpls_des_17 (R2= 0.8028, RMSE = 0.4884 and Q2 = 0.7661) was used to predict the pIC50 of the lead compounds. Internal and external validations were accessed to determine the predictive quality of the model. Finally the binding free energy calculation was computed. Results: The robustness/predictive quality of the models were affirmed. The hits had better binding affinity than the reference drug and interacted with key amino acids for PAK4 inhibition. Overall, the present analysis yielded three potential inhibitors that are predicted to bind with PAK4 better than reference drug tamoxifen. The three potent novel inhibitors vitexin, emodin and ziganein recorded IFD score of -621.97 kcal/mol, -616.31 kcal/mol and -614.95 kcal/mol, respectively while showing moderation for ADME properties and inhibition constant. Conclusion: It is expected that the findings reported in this study may provide insight for designing effective and less toxic PAK4 inhibitors for triple negative breast cancer.

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Natural Compounds and Drug Discovery: Can Cnidarian Venom Play a Role?

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524919666190227234834 ◽

2019 ◽

Vol 19 (2) ◽

pp. 114-118

Author(s):

Gian Luigi Mariottini ◽

Irwin Darren Grice

Keyword(s):

Biological Activity ◽

Marine Species ◽

Natural Compounds ◽

Therapeutic Agents ◽

Industrial Applications ◽

Bioactive Molecules ◽

Sea Anemones ◽

Therapeutic Approaches ◽

Ongoing Research ◽

Biological Compounds

Natural compounds extracted from organisms and microorganisms are an important resource for the development of drugs and bioactive molecules. Many such compounds have made valuable contributions in diverse fields such as human health, pharmaceutics and industrial applications. Presently, however, research on investigating natural compounds from marine organisms is scarce. This is somewhat surprising considering that the marine environment makes a major contribution to Earth's ecosystems and consequently possesses a vast storehouse of diverse marine species. Interestingly, of the marine bioactive natural compounds identified to date, many are venoms, coming from Cnidarians (jellyfish, sea anemones, corals). Cnidarians are therefore particularly interesting marine species, producing important biological compounds that warrant further investigation for their development as possible therapeutic agents. From an experimental aspect, this review aims to emphasize and update the current scientific knowledge reported on selected biological activity (antiinflammatory, antimicrobial, antitumoral, anticoagulant, along with several less studied effects) of Cnidarian venoms/extracts, highlighting potential aspects for ongoing research towards their utilization in human therapeutic approaches.

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Identification of potential inhibitors for Sterol C-24 reductase of Leishmania donovani through virtual screening of natural compounds

BIOCELL ◽

10.32604/biocell.2021.016682 ◽

2021 ◽

Vol 45 (6) ◽

pp. 1601-1610

Author(s):

FAZLUR RAHMAN ◽

SHAMS TABREZ ◽

RAHAT ALI ◽

SAJJADUL KADIR AKAND ◽

MOHAMMED A. ALAIDAROUS ◽

...

Keyword(s):

Virtual Screening ◽

Leishmania Donovani ◽

Natural Compounds ◽

Potential Inhibitors

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Amino Alcohols from Eugenol as Potential Semisynthetic Insecticides: Chemical, Biological, and Computational Insights

Molecules ◽

10.3390/molecules26216616 ◽

2021 ◽

Vol 26 (21) ◽

pp. 6616

Author(s):

Renato B. Pereira ◽

Nuno F. S. Pinto ◽

Maria José G. Fernandes ◽

Tatiana F. Vieira ◽

Ana Rita O. Rodrigues ◽

...

Keyword(s):

Molecular Dynamics ◽

Biological Activity ◽

Virtual Screening ◽

Serine Proteases ◽

Insect Cells ◽

Amino Alcohols ◽

Odorant Binding Proteins ◽

Synthetic Pesticide ◽

Dynamics Simulations ◽

Odorant Binding

A series of β-amino alcohols were prepared by the reaction of eugenol epoxide with aliphatic and aromatic amine nucleophiles. The synthesized compounds were fully characterized and evaluated as potential insecticides through the assessment of their biological activity against Sf9 insect cells, compared with a commercial synthetic pesticide (chlorpyrifos, CHPY). Three derivatives bearing a terminal benzene ring, either substituted or unsubstituted, were identified as the most potent molecules, two of them displaying higher toxicity to insect cells than CHPY. In addition, the most promising molecules were able to increase the activity of serine proteases (caspases) pivotal to apoptosis and were more toxic to insect cells than human cells. Structure-based inverted virtual screening and molecular dynamics simulations demonstrate that these molecules likely target acetylcholinesterase and/or the insect odorant-binding proteins and are able to form stable complexes with these proteins. Encapsulation assays in liposomes of DMPG and DPPC/DMPG (1:1) were performed for the most active compound, and high encapsulation efficiencies were obtained. A thermosensitive formulation was achieved with the compound release being more efficient at higher temperatures.

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Virtual screening of natural compounds as combinatorial agents from indian medicinal plants against estrogen positive breast cancer

International Journal on Integrated Education ◽

10.31149/ijie.v3i10.750 ◽

2020 ◽

Vol 3 (10) ◽

pp. 266-275

Author(s):

Shaleen Jain ◽

Dr. Asmita Das

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Virtual Screening ◽

Medicinal Plants ◽

Natural Compounds ◽

Binding Energies ◽

Common Amino Acid ◽

Estrogen Receptor Positive ◽

Positive Breast Cancer

Facing worldwide challenges associated with multifactorial etiology of breast cancer, designing of combinatorial therapies using natural compounds is currently the emergent way of treating several cancers including breast cancer in a synergistic way, which may mitigate several problems associated with multiple receptor targeting. In this research, Estrogen receptor positive breast cancer was taken as prototype and several key receptors associated with this particular disease were targeted by virtual screening of natural compounds found in Indian originated medicinal plants using Computer aided Drug Designing (CADD) strategies. We found the combination of Carpusin, Paulownin Cornigerine, Nororientaline, Oryzalexin B, Romucosine H and Colchicine as effective against six potential receptors i.e. FGFR2, ESR1, PIK3CA, PIK3CB, PIK3CD and AR in Estrogen receptor positive breast cancer with their binding energies in the range of ∆G ≤ -8.0 Kcal/mol as well as significant number of common amino acid binding residues as compared with binding sites of receptors. Thus this research holds significant implications for the designing of combinatorial therapeutic agents against breast cancer which can be further tested in-vitro and in-vivo to prove their synergistic efficiency.

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Targeting FGL2, a molecular drug target for glioblastoma, with natural compounds through virtual screening method

Future Medicinal Chemistry ◽

10.4155/fmc-2020-0331 ◽

2021 ◽

Author(s):

Fahad Hassan Shah ◽

Song Ja Kim

Keyword(s):

Virtual Screening ◽

Active Site ◽

Drug Target ◽

Screening Method ◽

Tumor Development ◽

Pharmacokinetic Profile ◽

Natural Compounds ◽

Screening Platform ◽

Proliferation In Vitro

Background: Fibroleukin-2 protein (FGL2) causes redevelopment of brain tumors. Inhibition of these proteins has shown to improve glioblastoma prognosis and treatment efficacy. Aim: The current study gathered recently exploited natural compounds that suppress glioblastoma proliferation in vitro, tested against FGL2 protein. Method: Twenty-five compounds were explored through a virtual screening platform. Results: Three natural compounds (betanine, hesperetin and ovatodiolide) hit the active site of FGL2. Furthermore, the influence of these compounds was also assessed using in silico gene expression, and ADMET tools showed downregulation of some genes, which caused rapid tumor development while possessing a moderate acute toxicity and pharmacokinetic profile. Conclusion: Our study presents three compounds that are good candidates for evaluation in FGL2 mutated glioblastoma animal models.

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