Ligand-Based Pharmacophore Modeling and Virtual Screening to Discover Novel CYP1A1 Inhibitors

2020 ◽  
Vol 19 (30) ◽  
pp. 2782-2794 ◽  
Author(s):  
Rana Adnan Tahir ◽  
Farwa Hassan ◽  
Abdul Kareem ◽  
Umer Iftikhar ◽  
Sheikh Arslan Sehgal
Keyword(s):  
Drug Target ◽  
Pharmacophore Modeling ◽  
Binding Affinities ◽  
The Novel ◽  
Fitness Score ◽  
Wide Range ◽  
Receptor Interactions ◽  
Cytochrome P450 Family ◽  
Specific Inhibitors

Background: Cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) is an imperative enzyme due to its immersion in the biotransformation of a wide range of drugs and other xenobiotics. The involvement of enzymes in drug metabolism indicates an effective drug target for the development of novel therapeutics. The discovery of CYP1A1 specific inhibitors would be of particular relevance for the clinical pharmacology. Method: In the current work, in silico approaches were utilized to identify the novel potential compounds through a diverse set of reported inhibitors against CYP1A1. A dataset of reported compounds against CYP1 belongs to 10 different classes (alkaloids, coumarins, flavonoids, natural compounds, synthetic inhibitors, drugs, MBI’s, PAHs, naphthoquinone and stilbenoids) was retrieved and utilized for the comparative molecular docking analyses followed by pharmacophore modeling. The total eleven novel compounds were scrutinized on the basis of the highest binding affinities and least binding energy values. Result: ZINC08792486 compound attained the highest gold fitness score of 90.11 against CYP1A1 among all the scrutinized molecules. Conclusion: It has been elucidated that the residues Phe-224, Gly-316 and Ala-317 were conserved in all ligand-receptor interactions and critical for the development of effective therapies. The ADMET property analyses also predict better absorption and distribution of the selected hits that may be used in the future for in vitro validations and drug development.

scholarly journals Millet Derived Flavonoids as Potential SARS-CoV-2 Main Protease Inhibitors: A Computational Approach

2020 ◽  
Author(s):  
Abhisek Mishra ◽  
Sobha Chnadra Rath ◽  
Iswar Baitharu ◽  
Bhawani Prasad Bag
Keyword(s):  
Drug Target ◽  
Hiv Protease ◽  
Binding Affinities ◽  
Autodock Vina ◽  
Major Health ◽  
Main Protease ◽  
Negative Effect ◽  
Mutagenic Property

The on-going pandemic COVID-19 has emerged as a major health threat across the globe. At present, anti-viral drug discoveries are of great importance in combating the pandemic. Millets are known to contain numerous flavonoids with potential anti-viral properties. However, their anti-viral efficacy against SARS-CoV-2 is yet to be studied. The study uses the SARS-CoV-2 main protease (M<sup>pro</sup>) as the potential drug target and docks with eleven millet derived flavonoids taking HIV protease inhibiting drugs nelfinavir and saquinavir as control. AutoDock Vina was used for assessing the binding affinities and strength of binding of flavonoids present in millets with the target protein M<sup>pro</sup>. Further, the drug-likeness and pharmacokinetics properties of these flavonoids were analyzed using admetSAR. The ADMET analysis showed that isoorientin, orientin, vitexin, meletin, catechin, and myricetin possess potential mutagenic property while daidzein could have a negative effect on reproductive making these compounds as poor candidates for drug development against SARS-CoV-2. Based on the docking result and positive ADMET properties, the present study infers that apigenin may be considered as a potential inhibitor of SARS-CoV-2 M<sup>pro</sup> and may be further investigated to test its anti-viral activities using <i>in-vitro</i> and <i>in-vivo</i> study.

scholarly journals Millet Derived Flavonoids as Potential SARS-CoV-2 Main Protease Inhibitors: A Computational Approach

2020 ◽  
Author(s):  
Abhisek Mishra ◽  
Sobha Chnadra Rath ◽  
Iswar Baitharu ◽  
Bhawani Prasad Bag
Keyword(s):  
Drug Target ◽  
Hiv Protease ◽  
Binding Affinities ◽  
Autodock Vina ◽  
Major Health ◽  
Main Protease ◽  
Negative Effect ◽  
Mutagenic Property

The on-going pandemic COVID-19 has emerged as a major health threat across the globe. At present, anti-viral drug discoveries are of great importance in combating the pandemic. Millets are known to contain numerous flavonoids with potential anti-viral properties. However, their anti-viral efficacy against SARS-CoV-2 is yet to be studied. The study uses the SARS-CoV-2 main protease (M<sup>pro</sup>) as the potential drug target and docks with eleven millet derived flavonoids taking HIV protease inhibiting drugs nelfinavir and saquinavir as control. AutoDock Vina was used for assessing the binding affinities and strength of binding of flavonoids present in millets with the target protein M<sup>pro</sup>. Further, the drug-likeness and pharmacokinetics properties of these flavonoids were analyzed using admetSAR. The ADMET analysis showed that isoorientin, orientin, vitexin, meletin, catechin, and myricetin possess potential mutagenic property while daidzein could have a negative effect on reproductive making these compounds as poor candidates for drug development against SARS-CoV-2. Based on the docking result and positive ADMET properties, the present study infers that apigenin may be considered as a potential inhibitor of SARS-CoV-2 M<sup>pro</sup> and may be further investigated to test its anti-viral activities using <i>in-vitro</i> and <i>in-vivo</i> study.

scholarly journals Perspectives on Precision Medicine in Chronic Lymphocytic Leukemia: Targeting Recurrent Mutations—NOTCH1, SF3B1, MYD88, BIRC3

2021 ◽  
Vol 10 (16) ◽  
pp. 3735
Author(s):  
Maciej Putowski ◽  
Krzysztof Giannopoulos
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Serum Markers ◽  
Primary Response ◽  
Lymphocytic Leukemia ◽  
The Novel ◽  
Recurrent Mutations ◽  
Receptor Interactions ◽  
Individualized Approach ◽  
Myd88 Pathway

Chronic lymphocytic leukemia (CLL) is highly heterogeneous, with extremely variable clinical course. The clinical heterogeneity of CLL reflects differences in the biology of the disease, including chromosomal alterations, specific immunophenotypic patterns and serum markers. The application of next-generation sequencing techniques has demonstrated the high genetic and epigenetic heterogeneity in CLL. The novel mutations could be pharmacologically targeted for individualized approach in some of the CLL patients. Potential neurogenic locus notch homolog protein 1 (NOTCH1) signalling targeting mechanisms in CLL include secretase inhibitors and specific antibodies to block NOTCH ligand/receptor interactions. In vitro studies characterizing the effect of the splicing inhibitors resulted in increased apoptosis of CLL cells regardless of splicing factor 3B subunit 1 (SF3B1) status. Several therapeutic strategies have been also proposed to directly or indirectly inhibit the toll-like receptor/myeloid differentiation primary response gene 88 (TLR/MyD88) pathway. Another potential approach is targeting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and inhibition of this prosurvival pathway. Newly discovered mutations and their signalling pathways play key roles in the course of the disease. This opens new opportunities in the management and treatment of CLL.

scholarly journals Differential recognition of opioid analgesics by µ opioid receptors: Predicted interaction patterns correlate with ligand-specific voltage sensitivity

2021 ◽  
Author(s):  
Sina B. Kirchhofer ◽  
Victor Jun Yu Lim ◽  
Julia G. Ruland ◽  
Peter Kolb ◽  
Moritz Bünemann
Keyword(s):  
Opioid Analgesics ◽  
Receptor Activation ◽  
Voltage Sensitivity ◽  
Interaction Patterns ◽  
Binding Modes ◽  
Cellular Assays ◽  
Specific Effects ◽  
Wide Range ◽  
Receptor Interactions

AbstractThe µ opioid receptor (MOR) is the key target for analgesia, but the application of opioids is accompanied by several issues. There is a wide range of opioid analgesics, differing in their chemical structure and their properties in receptor activation and subsequent effects. A better understanding of ligand-receptor interactions and resulting effects is important. Here, we calculated the respective binding modes for several opioids and analyzed fingerprints of ligand-receptor interactions. We further corroborated the binding modes experimentally by cellular assays. As ligand-induced modulation of activity due to changes in membrane potential was displayed by MOR, we further analyzed the effects of voltage sensitivity of this receptor. With a combined in silico and in vitro approach, we defined discriminating interaction patterns for the ligand-specific voltage sensitivity. With this, we present new insights for interactions likely in ligand recognition and their specific effects on activation of the MOR.

scholarly journals Newly Synthesized Fluorinated Cinnamylpiperazines Possessing Low In Vitro MAO-B Binding

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4941
Author(s):  
Ivana I. Jevtić ◽  
Thu Hang Lai ◽  
Jelena Z. Penjišević ◽  
Sladjana Dukić-Stefanović ◽  
Deana B. Andrić ◽  
...  
Keyword(s):  
Binding Assay ◽  
Docking Studies ◽  
Emission Tomography ◽  
Binding Affinities ◽  
The Novel ◽  
Competitive Binding Assay ◽  
Mao B ◽  
Positron Emission ◽  
Further Development

Herein, we report on the synthesis and pharmacological evaluation of ten novel fluorinated cinnamylpiperazines as potential monoamine oxidase B (MAO-B) ligands. The designed derivatives consist of either cinnamyl or 2-fluorocinnamyl moieties connected to 2-fluoropyridylpiperazines. The three-step synthesis starting from commercially available piperazine afforded the final products in overall yields between 9% and 29%. An in vitro competitive binding assay using l-[3H]Deprenyl as radioligand was developed and the MAO-B binding affinities of the synthesized derivatives were assessed. Docking studies revealed that the compounds 8–17 were stabilized in both MAO-B entrance and substrate cavities, thus resembling the binding pose of l-Deprenyl. Although our results revealed that the novel fluorinated cinnamylpiperazines 8–17 do not possess sufficient MAO-B binding affinity to be eligible as positron emission tomography (PET) agents, the herein developed binding assay and the insights gained within our docking studies will certainly pave the way for further development of MAO-B ligands.

scholarly journals Synthesis of Novel 2-(Pyridin-2-yl) Pyrimidine Derivatives and Study of Their Anti-Fibrosis Activity

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5226
Author(s):  
Yi-Fei Gu ◽  
Yue Zhang ◽  
Feng-li Yue ◽  
Shao-tong Li ◽  
Zhuo-qi Zhang ◽  
...  
Keyword(s):  
Biological Activities ◽  
Collagen Type I ◽  
Type I ◽  
The Novel ◽  
Pyrimidine Derivatives ◽  
Wide Range ◽  
Ic50 Values ◽  
Privileged Structures ◽  
Pyrimidine Moiety

A pyrimidine moiety exhibiting a wide range of pharmacological activities has been employed in the design of privileged structures in medicinal chemistry. To prepare libraries of novel heterocyclic compounds with potential biological activities, a series of novel 2-(pyridin-2-yl) pyrimidine derivatives were designed, synthesized and their biological activities were evaluated against immortalized rat hepatic stellate cells (HSC-T6). Fourteen compounds were found to present better anti-fibrotic activities than Pirfenidone and Bipy55′DC. Among them, compounds ethyl 6-(5-(p-tolylcarbamoyl)pyrimidin-2-yl)nicotinate (12m) and ethyl 6-(5-((3,4-difluorophenyl)carbamoyl)pyrimidin-2-yl)nicotinate (12q) show the best activities with IC50 values of 45.69 μM and 45.81 μM, respectively. Furthermore, the study of anti-fibrosis activity was evaluated by Picro-Sirius red staining, hydroxyproline assay and ELISA detection of Collagen type I alpha 1 (COL1A1) protein expression. Our study showed that compounds 12m and 12q effectively inhibited the expression of collagen, and the content of hydroxyproline in cell culture medium in vitro, indicating that compounds 12m and 12q might be developed the novel anti-fibrotic drugs.

Lactoferrin as potential preventative and treatment for COVID-19

2020 ◽  
Author(s):  
Raymond Chang ◽  
Wei-Zen Sun ◽  
Tzi Bun Ng
Keyword(s):  
Nutritional Supplement ◽  
Personal Health ◽  
The Novel ◽  
Adjunct Treatment ◽  
Health Measures ◽  
Naturally Occurring ◽  
Wide Range ◽  
Novel Coronavirus ◽  
Unique Potential

The novel coronavirus 2019 (COVID-19) pandemic is rapidly advancing across the globe despite public and personal health measures. Antivirals and nutritional supplements have been proposed as potentially useful against SARS-CoV-2 (virus that causes COVID-19), but few have been clinically established. Lactoferrin (Lf) is a naturally occurring and non-toxic glycoprotein that is orally available as a nutritional supplement and has established in vitro anti-viral efficacy against a wide range of virus including SARS-CoV, a closely related corona virus to SARS-CoV-2 (virus that causes COVID-19). Furthermore, Lf possesses unique immunomodulatory and anti-inflammatory effects that maybe especially relevant to the pathophysiology of severe COVID-19 cases. We review the underlying biological mechanisms of Lf as antiviral and immune regulator, and propose its unique potential as preventative and adjunct treatment for COVID-19. We hope that further research and development of Lf nutritional supplementation would establish its role for COVID-19.

scholarly journals 2-Arylidene-1-indandiones as Pleiotropic Agents with Antioxidant and Inhibitory Enzymes Activities

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4411 ◽  
Author(s):  
Olympia Kouzi ◽  
Eleni Pontiki ◽  
Dimitra Hadjipavlou-Litina
Keyword(s):  
Antioxidant Activities ◽  
Biological Activities ◽  
Knoevenagel Reaction ◽  
The Novel ◽  
Hydrophobic Domain ◽  
Antioxidant Agents ◽  
Wide Range ◽  
Anti Inflammatory

Indandiones are a relatively new group of compounds presenting a wide range of biological activities. The synthesis of these compounds was performed via a Knoevenagel reaction between an aldehyde and 1,3-indandione and were obtained with a yield up to 54%. IR, 1H-Nucleic Magnetic Resonance (NMR), 13C-NMR, LC/MS ESI+ and elemental analysis were used for the confirmation of the structures of the novel derivatives. Lipophilicity values of compounds were calculated theoretically and experimentally by reversed chromatography method as values RM. The novel derivatives were studied through in vitro and in vivo experiments for their activity as anti-inflammatory and antioxidant agents and as inhibitors of lipoxygenase, trypsin, and thrombin. The inhibition of the carrageenin-induced paw edema (CPE) was also determined for representative structures. In the above series of experiments, we find that all the compounds showed moderate to satisfying interaction with the stable DPPH free radical in relation to the concentration and the time 2-arylidene-1-indandione (10) was the strongest. We observed moderate or very low antioxidant activities for selected compounds in the decolorization assay with ABTS+•. Most of the compounds showed high anti-lipid peroxidation of linoleic acid induced by AAPH.2-arylidene-1-indandione (7) showed a strongly inhibited soybean LOX. Only 2-arylidene-1-indandione (3) showed moderate scavenging activity of superoxide anion, whereas 2-arylidene-1-indandione (8) and 2-arylidene-1-indandione (9) showed very strong inhibition on proteolysis. 2-arylidene-1-indandione (8) highly inhibited serine protease thrombin. 2-arylidene-1-indandiones (7, 8 and 9) can be used as lead multifunctional molecules. The compounds were active for the inhibition of the CPE (30–57%) with 2-arylidene-1-indandione (1) being the most potent (57%). According to the predicted results a great number of the derivatives can cross the Blood–Brain Barrier (BBB), act in CNS and easily transported, diffused, and absorbed. Efforts are conducted a) to correlate quantitatively the in vitro/in vivo results with the most important physicochemical properties of the structural components of the molecules and b) to clarify the correlation of actions among them to propose a possible mechanism of action. Hydration energy as EHYDR and highest occupied molecular orbital (HOMO) better describe their antioxidant profile whereas the lipophilicity as RM values governs the in vivo anti-inflammatory activity. Docking studies are performed and showed that soybean LOX oxidation was prevented by blocking into the hydrophobic domain the substrates to the active site.

scholarly journals 5-(4H)-Oxazolones and Their Benzamides as Potential Bioactive Small Molecules

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3173
Author(s):  
Evangelos Mavridis ◽  
Eleftherios Bermperoglou ◽  
Eleni Pontiki ◽  
Dimitra Hadjipavlou-Litina
Keyword(s):  
Lipid Peroxidation ◽  
Biological Activities ◽  
Phenyl Group ◽  
Docking Studies ◽  
Nucleophilic Attack ◽  
The Novel ◽  
Lipoxygenase Inhibitor ◽  
Wide Range ◽  
Inhibit Lipid Peroxidation

The five membered heterocyclic oxazole group plays an important role in drug discovery. Oxazolones present a wide range of biological activities. In this article the synthesis of 4-substituted-2-phenyloxazol-5(4H)-ones from the appropriate substituted aldehydes via an Erlenmeyer–Plochl reaction is reported. Subsequently, the corresponding benzamides were produced via a nucleophilic attack of a secondary amine on the oxazolone ring applying microwave irradiation. The compounds are obtained in good yields up to 94% and their structures were confirmed using IR, 1H-NMR, 13C-NMR and LC/MS data. The in vitro anti-lipid peroxidation activity and inhibitory activity against lipoxygenase and trypsin induced proteolysis of the novel derivatives were studied. Inhibition of carrageenin-induced paw edema (CPE) and nociception was also determined for compounds 4a and 4c. Oxazolones 2a and 2c strongly inhibit lipid peroxidation, followed by oxazolones 2b and 2d with an average inhibition of 86.5%. The most potent lipoxygenase inhibitor was the bisbenzamide derivative 4c, with IC50 41 μM. The benzamides 3c, 4a–4e and 5c were strong inhibitors of proteolysis. The replacement of the thienyl moiety by a phenyl group does not favor the protection. Compound 4c inhibited nociception higher than 4a. The replacement of thienyl groups by phenyl ring led to reduced biological activity. Docking studies of the most potent LOX inhibitor highlight interactions through allosteric mechanism. All the potent derivatives present good oral bioavailability.

scholarly journals BCR-ABL Tyrosine Kinase Inhibitors as Candidates for the Treatment of COVID-19: Molecular Docking, Pharmacophore Modeling, ADMET Studies

2021 ◽  
Vol 12 (3) ◽  
pp. 3357-3371
Keyword(s):  
Energy Balance ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Pharmacophore Modeling ◽  
The Novel ◽  
Abl Tyrosine Kinase ◽  
In Silico Modeling ◽  
Novel Coronavirus ◽  
Viral Target

The novel coronavirus pandemic (COVID-19) caused by SARS-CoV-2 has affected more than 53 million individuals worldwide. Currently, there is a dire need to develop or find potential drugs that can treat SARS-CoV-2 infection. One of the standard methods to accelerate drug discovery and development in pandemics is to screen currently available medications against the critical therapeutic targets to find potential therapeutic agents. The literature has pointed out the 3CLpro and RdRp proteins as the most important proteins involved in viral replications. In the present study, we used an in-silico modeling approach to examine the affinity of six tyrosine kinases inhibitors (TKIs), Imatinib, Ponatinib, Nilotinib, Gefitinib, Erlotinib, and Dasatinibagainst the 3CLpro and RdRp by calculating the energy balance. The six tested TKIs had more than -7 Kcal/mol energy balance values for both viral target proteins. Nilotinib and Ponatinib showed the highest affinity for 3CLpro (-8.32, -8.16, respectively) while Dasatinib, Ponatinib, and Imatinib presented the strongest binding toRdRp(-14.50, -10.57, -9.46, respectively). Based on these findings, we recommend future evaluations of TKIs for SARs-CoV-2 infection in-vitro and further testing in clinical trials.

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