Virtual screening in drug-likeness and structure/activity relationship of pyridazine derivatives as Anti-Alzheimer drugs

Zerroug, Enfale; Belaidi, Salah; BenBrahim, Imane; Sinha, Leena; Chtita, Samir

doi:10.1016/j.jksus.2018.03.024

Cited by 54 publications

(43 citation statements)

References 37 publications

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“…The compounds were physicochemically profiled using Swiss ADME and OSIRIS Property Explorer. RO5, Ghose and Veber’s rules were used to evaluate the drug-likeness of the compounds [ 87 ]. Most of the compounds that violated more than one drug-like parameter were eliminated from the study ( Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

Computational Study on Potential Novel Anti-Ebola Virus Protein VP35 Natural Compounds

et al. 2021

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Ebola virus (EBOV) is one of the most lethal pathogens that can infect humans. The Ebola viral protein VP35 (EBOV VP35) inhibits host IFN-α/β production by interfering with host immune responses to viral invasion and is thus considered as a plausible drug target. The aim of this study was to identify potential novel lead compounds against EBOV VP35 using computational techniques in drug discovery. The 3D structure of the EBOV VP35 with PDB ID: 3FKE was used for molecular docking studies. An integrated library of 7675 African natural product was pre-filtered using ADMET risk, with a threshold of 7 and, as a result, 1470 ligands were obtained for the downstream molecular docking using AutoDock Vina, after an energy minimization of the protein via GROMACS. Five known inhibitors, namely, amodiaquine, chloroquine, gossypetin, taxifolin and EGCG were used as standard control compounds for this study. The area under the curve (AUC) value, evaluating the docking protocol obtained from the receiver operating characteristic (ROC) curve, generated was 0.72, which was considered to be acceptable. The four identified potential lead compounds of NANPDB4048, NANPDB2412, ZINC000095486250 and NANPDB2476 had binding affinities of −8.2, −8.2, −8.1 and −8.0 kcal/mol, respectively, and were predicted to possess desirable antiviral activity including the inhibition of RNA synthesis and membrane permeability, with the probable activity (Pa) being greater than the probable inactivity (Pi) values. The predicted anti-EBOV inhibition efficiency values (IC50), found using a random forest classifier, ranged from 3.35 to 11.99 μM, while the Ki values ranged from 0.97 to 1.37 μM. The compounds NANPDB4048 and NANPDB2412 had the lowest binding energy of −8.2 kcal/mol, implying a higher binding affinity to EBOV VP35 which was greater than those of the known inhibitors. The compounds were predicted to possess a low toxicity risk and to possess reasonably good pharmacological profiles. Molecular dynamics (MD) simulations of the protein–ligand complexes, lasting 50 ns, and molecular mechanisms Poisson-Boltzmann surface area (MM-PBSA) calculations corroborated the binding affinities of the identified compounds and identified novel critical interacting residues. The antiviral potential of the molecules could be confirmed experimentally, while the scaffolds could be optimized for the design of future novel anti-EBOV chemotherapeutics.

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Section: Resultsmentioning

confidence: 99%

Computational Study on Potential Novel Anti-Ebola Virus Protein VP35 Natural Compounds

et al. 2021

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“…Virtual screening (VS) is the process of screening small molecule libraries in silico to identify chemical structures that may bind to a drug target [ 31 , 32 , 33 ].…”

Section: Computer-aided Drug Designmentioning

confidence: 99%

Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases

Salman

Al-Obaidi

Kitchen

et al. 2021

IJMS

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Neurodegenerative diseases (NDs) including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools.

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“…All the molecules studied were analyzed in silico for their molecular properties and drug-likeness limits. It was constructed using hypothetical approaches with the aim of identifying molecules that meet the ideal criteria for exhibiting as drug-like molecules as described by Lipinski's rule of five [25], and other physicochemical parameters were considered using the Biovia DS vs. 4.5 software module "Calculation of Molecular Properties". Additionally, specific properties were predicted using open web-based resources, such as Molsoft (http://www.molsoft.com/, accessed on 15 February 2021) and the computer app Molinspiration.…”

Section: Computational Analysis 281 Drug-likeness Studiesmentioning

confidence: 99%

In Vitro and In Silico Toxicological Properties of Natural Antioxidant Therapeutic Agent Azima tetracantha. LAM

Prakash

Kumari

Gayathiri³

et al. 2021

Antioxidants

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Plant-derived antioxidants are a large group of natural products with the capacity to reduce radical-scavenging. Due to their potent therapeutic and preventive actions, these compounds receive a lot of attention from scientists, particularly pharmacologists. The pharmacological activities of the Azima tetracantha Lam. (AT) plant, belonging to the Salvadoraceae family, reported here justifies its traditional use in treating several diseases or disorders. This study aims to look at the propensity of certain plant compounds found in natural AT plant extracts that might play a critical role as a secondary metabolite in cervical cancer treatment. There is a shortage of information on the plant’s phytochemical and biological characteristics. Methanol (MeOH) solvent extracts of the dried AT plant were screened phytochemically. Its aqueous extract was tested for antioxidant, antiseptic, anti-inflammatory, and anticancerous properties. Absorption Distribution Metabolism and Excretion (ADME/T), Docking, and HPLC were also performed. In clinical treatment, the plant shown no adverse effects. The antioxidant activity was evaluated and showed the highest concentration at 150 µg/mL (63.50%). MeOH leaf extract of AT exhibited the highest and best inhibitory activity against Staphylococcus aureus (15.3 mm/1000) and displayed a high antiseptic potential. At a 200 µg/mL concentration, MeOH leaves-extract inhibited red blood cells (RBC) hemolysis by 66.56 ± 0.40, compared with 62.33 ± 0.40 from the standard. Albumin’s ability to suppress protein denaturation ranged from 16.75 ± 0.65 to 62.35 ± 0.20 inhibitions in this test, providing even more support for its favorable anti-inflammatory properties. The ADME/T studies were considered for a potential cancer drug molecule, and one of our compounds from MeOH extract fills the ADME and toxicity parameters. The forms of compound 4 showed a strong hydrogen-bonding interaction with the vital amino acids (ASN923, THR410, LEU840TRY927, PHE921, and GLY922). A total of 90% of cell inhibition was observed when HeLa cell lines were treated with 300 µg/mL of compound 4 (7-acetyl-3a1-methyl- 4,14-dioxo-1,2,3a,3a1,4,5,5a,6,8a,9b,10,11,11a-tetradecahydro-2,5a epoxy5,6a (methanooxymethano)phenaleno[1′,9′:5,6,7]indeno[1,7a-b]oxiren-2-yl acetate). The polyphenol compounds demonstrated significant advances in anticancer drug properties, and it could lead to activation of cancer cell apoptosis.

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Virtual screening in drug-likeness and structure/activity relationship of pyridazine derivatives as Anti-Alzheimer drugs

Cited by 54 publications

References 37 publications

Computational Study on Potential Novel Anti-Ebola Virus Protein VP35 Natural Compounds

Computational Study on Potential Novel Anti-Ebola Virus Protein VP35 Natural Compounds

Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases

In Vitro and In Silico Toxicological Properties of Natural Antioxidant Therapeutic Agent Azima tetracantha. LAM

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