An Integrated Pharmacophore/Docking/3D-QSAR Approach to Screening a Large Library of Products in Search of Future Botulinum Neurotoxin A Inhibitors

Botulinum toxins are neurotoxins produced by Clostridium botulinum. This toxin can be lethal for humans as a cause of botulism; however, in small doses, the same toxin is used to treat different conditions. Even if the therapeutic doses are effective and safe, the adverse reactions could be local and could unmask a subclinical impairment of neuromuscular transmissions. There are not many cases of adverse events in the literature; however, it is possible that sometimes they do not occur as they are transient and, if they do occur, there is no possibility of a cure other than to wait for the pharmacological effect to end. Inhibition of botulinum neurotoxin type A (BoNT/A) effects is a strategy for treating botulism as it can provide an effective post-exposure remedy. In this paper, 13,592,287 compounds were screened through a pharmacophore filter, a 3D-QSAR model, and a virtual screening; then, the compounds with the best affinity were selected. Molecular dynamics simulation studies on the first four compounds predicted to be the most active were conducted to verify that the poses foreseen by the docking were stable. This approach allowed us to identify compounds with a calculated inhibitory activity in the range of 316–500 nM.

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Simulation studies, 3D QSAR and molecular docking on a point mutation of protein kinase B with flavonoids targeting ovarian Cancer

BMC Pharmacology and Toxicology ◽

10.1186/s40360-021-00512-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Suchitra Maheswari Ajjarapu ◽

Apoorv Tiwari ◽

Gohar Taj ◽

Dev Bukhsh Singh ◽

Sakshi Singh ◽

...

Keyword(s):

Ovarian Cancer ◽

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulation ◽

Protein Kinase ◽

Point Mutation ◽

Protein Kinase B ◽

3D Qsar ◽

Dynamics Simulation ◽

Simulation Studies

Abstract Background Ovarian cancer is the world’s dreaded disease and its prevalence is expanding globally. The study of integrated molecular networks is crucial for the basic mechanism of cancer cells and their progression. During the present investigation, we have examined different flavonoids that target protein kinases B (AKT1) protein which exerts their anticancer efficiency intriguing the role in cross-talk cell signalling, by metabolic processes through in-silico approaches. Method Molecular dynamics simulation (MDS) was performed to analyze and evaluate the stability of the complexes under physiological conditions and the results were congruent with molecular docking. This investigation revealed the effect of a point mutation (W80R), considered based on their frequency of occurrence, with AKT1 protein. Results The ligand with high docking scores and favourable behaviour on dynamic simulations are proposed as potential W80R inhibitors. A virtual screening analysis was performed with 12,000 flavonoids satisfying Lipinski’s rule of five according to which drug-likeness is predicted based on its pharmacological and biological properties to be active and taken orally. The pharmacokinetic ADME (adsorption, digestion, metabolism, and excretion) studies featured drug-likeness. Subsequently, a statistically significant 3D-QSAR model of high correlation coefficient (R2) with 0.822 and cross-validation coefficient (Q2) with 0.6132 at 4 component PLS (partial least square) were used to verify the accuracy of the models. Taxifolin holds good interactions with the binding domain of W80R, highest Glide score of − 9.63 kcal/mol with OH of GLU234 and H bond ASP274 and LEU156 amino acid residues and one pi-cation interaction and one hydrophobic bond with LYS276. Conclusion Natural compounds have always been a richest source of active compounds with a wide variety of structures, therefore, these compounds showed a special inspiration for medical chemists. The present study has aimed molecular docking and molecular dynamics simulation studies on taxifolin targeting W80R mutant protein of protein kinase B/serine- threonine kinase/AKT1 (EC:2.7.11.1) protein of ovarian cancer for designing therapeutic intervention. The expected result supported the molecular cause in a mutant form which resulted in a gain of ovarian cancer. Here we discussed validations computationally and yet experimental evaluation or in vivo studies are endorsed for further study. Several of these compounds should become the next marvels for early detection of ovarian cancer.

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Extended N-Terminal Protein Sequencing of Clostridium botulinum Neurotoxin Type A Fragments: Continuous Sequence to Seventy Residues Both from Glass-Fiber Filter Using the Gas Phase and Polyvinylidene Difluoride Using the Pulsed Liquid Phase Sequencer

Current Research in Protein Chemistry ◽

10.1016/b978-0-12-721955-4.50022-1 ◽

1990 ◽

pp. 167-178 ◽

Cited By ~ 1

Author(s):

Cynthia L. Wadsworth ◽

Ronald L. Niece ◽

Juan A. Gimenez ◽

Bibhuti R. DasGupta

Keyword(s):

Liquid Phase ◽

Glass Fiber ◽

Clostridium Botulinum ◽

Botulinum Neurotoxin ◽

Protein Sequencing ◽

Terminal Protein ◽

Polyvinylidene Difluoride ◽

Glass Fiber Filter ◽

Botulinum Neurotoxin Type A ◽

Continuous Sequence

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Enhanced Biodegradation of Phthalic Acid Esters’ Derivatives by Plasticizer-Degrading Bacteria (Burkholderia cepacia, Archaeoglobus fulgidus, Pseudomonas aeruginosa) Using a Correction 3D-QSAR Model

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17155299 ◽

2020 ◽

Vol 17 (15) ◽

pp. 5299

Author(s):

Haigang Zhang ◽

Chengji Zhao ◽

Hui Na

Keyword(s):

Pseudomonas Aeruginosa ◽

Burkholderia Cepacia ◽

Energy Barrier ◽

Phthalic Acid ◽

Similarity Index ◽

3D Qsar ◽

Qsar Model ◽

Dynamics Simulation ◽

Archaeoglobus Fulgidus ◽

Degrading Bacteria

A phthalic acid ester’s (PAEs) comprehensive biodegradability three-dimensional structure-activity relationship (3D-QSAR) model was established, to design environmentally friendly PAE derivatives, which could be simultaneously degraded by plasticizer-degrading bacteria, such as Burkholderia cepacia, Archaeoglobus fulgidus, and Pseudomonas aeruginosa. Only three derivatives of diethyl phthalate (DEP (DEP-27, DEP-28 and DEP-29)) were suited for their functionality and environmental friendliness, which had an improved stability in the environment and improved the characteristics (bio-toxicity, bioaccumulation, persistence, and long-range migration) of the persistent organic pollutants (POPs). The simulation inference of the microbial degradation path before and after DEP modification and the calculation of the reaction energy barrier exhibited the energy barrier for degradation being reduced after DEP modification and was consistent with the increased ratio of comprehensive biodegradability. This confirmed the effectiveness of the comparative molecular similarity index analysis (CoMSIA) model of the PAE’s comprehensive biodegradability. In addition, a molecular dynamics simulation revealed that the binding of the DEP-29 derivative with the three plasticizer-degradation enzymes increased significantly. DEP-29 could be used as a methyl phthalate derivative that synergistically degrades with microplastics, providing directional selection and theoretical designing for plasticizer replacement.

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