Structure-Based Design, Synthesis and Molecular Modeling Studies of Thiazolyl Urea Derivatives as Novel Anti-Parkinsonian Agents

Azam, Faizul; Prasad, Medapati Vijaya Vara; Thangavel, Neelaveni; Shrivastava, Anil Kumar; Mohan, G. Krishna

doi:10.2174/1573406411208061057

Cited by 12 publications

(6 citation statements)

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“…Also, Actinomycin D co-crystallized with DNA fragment (PDB ID: 1MNV) was also included in the study. Biovia Discovery Studio Visualizer 2020 and MGLTools 1.5.6 were used for the preparation of receptors 88 .…”

Section: Methodsmentioning

confidence: 99%

Isolation, characterization, anti-MRSA evaluation, and in-silico multi-target anti-microbial validations of actinomycin X2 and actinomycin D produced by novel Streptomyces smyrnaeus UKAQ_23

Qureshi

Bholay

Pankaj

et al. 2021

Sci Rep

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Streptomyces smyrnaeus UKAQ_23, isolated from the mangrove-sediment, collected from Jubail,Saudi Arabia, exhibited substantial antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), including non-MRSA Gram-positive test bacteria. The novel isolate, under laboratory-scale conditions, produced the highest yield (561.3 ± 0.3 mg/kg fermented agar) of antimicrobial compounds in modified ISP-4 agar at pH 6.5, temperature 35 °C, inoculum 5% v/w, agar 1.5% w/v, and an incubation period of 7 days. The two major compounds, K1 and K2, were isolated from fermented medium and identified as Actinomycin X2 and Actinomycin D, respectively, based on their structural analysis. The antimicrobial screening showed that Actinomycin X2 had the highest antimicrobial activity compared to Actinomycin D, and the actinomycins-mixture (X2:D, 1:1, w/w) against MRSA and non-MRSA Gram-positive test bacteria, at 5 µg/disc concentrations. The MIC of Actinomycin X2 ranged from 1.56–12.5 µg/ml for non-MRSA and 3.125–12.5 µg/ml for MRSA test bacteria. An in-silico molecular docking demonstrated isoleucyl tRNA synthetase as the most-favored antimicrobial protein target for both actinomycins, X2 and D, while the penicillin-binding protein-1a, was the least-favorable target-protein. In conclusion, Streptomyces smyrnaeus UKAQ_23 emerged as a promising source of Actinomycin X2 with the potential to be scaled up for industrial production, which could benefit the pharmaceutical industry.

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Section: Methodsmentioning

confidence: 99%

Isolation, characterization, anti-MRSA evaluation, and in-silico multi-target anti-microbial validations of actinomycin X2 and actinomycin D produced by novel Streptomyces smyrnaeus UKAQ_23

Qureshi

Bholay

Pankaj

et al. 2021

Sci Rep

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“…Other parameters of docking were set to default while exhaustiveness value was adjusted to 12 (Trott & Olson, 2010 ). At the end of docking, 10 best poses obtained from each target were analyzed individually for binding energy, intermolecular interactions and number in clusters using Biovia Discovery Studio Visualizer 2020, and PyMol 1.7.4 programs (Ahmed et al, 2012 ; Azam et al, 2012 ; Fahmy et al, 2020 ). Ten best poses of IVM obtained from AutoDock Vina 1.1 in complex with each target were further subjected to Molecular mechanics/generalized Born surface area (MM-GBSA) computations.…”

Section: Methodsmentioning

confidence: 99%

Anin-silicoanalysis of ivermectin interaction with potential SARS-CoV-2 targets and host nuclear importin α

Azam

Taban

Eid

et al. 2020

Journal of Biomolecular Structure and Dynamics

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Ivermectin (IVM) is a broad-spectrum antiparasitic agent, having inhibitory potential against wide range of viral infections. It has also been found to hamper SARS-CoV-2 replication in vitro, and its precise mechanism of action against SARS-CoV-2 is yet to be understood. IVM is known to interact with host importin (IMP)α directly and averts interaction with IMPβ1, leading to the prevention of nuclear localization signal (NLS) recognition. Therefore, the current study seeks to employ molecular docking, molecular mechanics generalized Born surface area (MM-GBSA) analysis and molecular dynamics simulation studies for decrypting the binding mode, key interacting residues as well as mechanistic insights on IVM interaction with 15 potential drug targets associated with COVID-19 as well as IMPα. Among all COVID-19 targets, the non-structural protein 9 (Nsp9) exhibited the strongest affinity to IVM showing −5.30 kcal/mol and −84.85 kcal/mol binding energies estimated by AutoDock Vina and MM-GBSA, respectively. However, moderate affinity was accounted for IMPα amounting −6.9 kcal/mol and −66.04 kcal/mol. Stability of the protein-ligand complexes of Nsp9-IVM and IMPα-IVM was ascertained by 100 ns trajectory of all-atom molecular dynamics simulation. Structural conformation of protein in complex with docked IVM exhibited stable root mean square deviation while root mean square fluctuations were also found to be consistent. In silico exploration of the potential targets and their interaction profile with IVM can assist experimental studies as well as designing of COVID-19 drugs. Communicated by Ramaswamy H. Sarma

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“…Urea derivatives consistently demonstrate conformation to the rule of five, exhibiting low calculated Log P values and a molecular weight less than 500 g/mol, in addition to being highly soluble and stable (Azam et al. 2012 ; Mannam et al. 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Diabetes mellitus drug discovery: insights into targeting feline and human amylin with small molecules

Moore,

Horgan,

Lenters

et al. 2023

Veterinary Quarterly

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Background Type 2 diabetes (T2D) is a health concern for both humans and cats, with cases rising over the past decade. Around 70% of patients from either species exhibit pancreatic aggregates of islet amyloid polypeptide (IAPP), a protein that proves toxic upon misfolding. These misfolded protein aggregates congregate in the islets of Langerhans of the pancreas, diminishing the capability of β-cells to produce insulin and further perpetuating disease. Objective Our team’s drug discovery program is investigating newly synthesized compounds that could diminish aggregates of both human and feline IAPP, potentially disrupting the progression of T2D. Material and methods We prepared 24 compounds derived from diaryl urea, as ureas have previously demonstrated great potential at reducing accumulations of misfolded proteins. Biophysical methods were employed to analyze the anti-aggregation activity of these compounds at inhibiting and/or disrupting IAPP fibril formation in vitro . Results The results demonstrate that compounds 12 and 24 were most effective at reducing the fibrillization and aggregation of both human and feline IAPP. When compared with the control for each experiment, samples treated with either compound 12 or 24 exhibited fewer accumulations of amyloid-like fibrils. Conclusion Urea-based compounds, such as compounds 12 and 24 , may prove crucial in future pre-clinical studies in the search for therapeutics for T2D.

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Structure-Based Design, Synthesis and Molecular Modeling Studies of Thiazolyl Urea Derivatives as Novel Anti-Parkinsonian Agents

Cited by 12 publications

References 0 publications

Isolation, characterization, anti-MRSA evaluation, and in-silico multi-target anti-microbial validations of actinomycin X2 and actinomycin D produced by novel Streptomyces smyrnaeus UKAQ_23

Isolation, characterization, anti-MRSA evaluation, and in-silico multi-target anti-microbial validations of actinomycin X2 and actinomycin D produced by novel Streptomyces smyrnaeus UKAQ_23

Anin-silicoanalysis of ivermectin interaction with potential SARS-CoV-2 targets and host nuclear importin α

Diabetes mellitus drug discovery: insights into targeting feline and human amylin with small molecules

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