Multi-targeted molecular docking,drug-likeness and ADMET studies of derivatives of few quinoline- and acridine-based FDA-approved drugs for anti-breast cancer activity

Structural Chemistry - Quinoline- and acridine-based drugs are widely used as anti-breast cancer agents. These drugs act through various mechanisms of action; for example, neratinib acts on...     

Structural insight into the inactivation of <Emphasis Type="Italic">Mycobacterium tuberculosis</Emphasis> non-classical transpeptidase Ldt<Subscript>Mt2</Subscript> by biapenem and tebipenem

Background

The carbapenem subclass of β-lactams is among the most potent antibiotics available today. Emerging evidence shows that, unlike other subclasses of β-lactams, carbapenems bind to and inhibit non-classical transpeptidases (L,D-transpeptidases) that generate 3 → 3 linkages in bacterial peptidoglycan. The carbapenems biapenem and tebipenem exhibit therapeutically valuable potencies against Mycobacterium tuberculosis (Mtb).

Results

Here, we report the X-ray crystal structures of Mtb L,D-transpeptidase-2 (Ldt_Mt2) complexed with biapenem or tebipenem. Despite significant variations in carbapenem sulfur side chains, biapenem and tebipenem ultimately form an identical adduct that docks to the outer cavity of Ldt_Mt2. We propose that this common adduct is an enzyme catalyzed decomposition of the carbapenem adduct by a mechanism similar to S-conjugate elimination by β-lyases.

Conclusion

The results presented here demonstrate biapenem and tebipenem bind to the outer cavity of Ldt_Mt2, covalently inactivate the enzyme, and subsequently degrade via an S-conjugate elimination mechanism. We discuss structure based drug design based on the findings and propose that the S-conjugate elimination can be leveraged to design novel agents to deliver and locally release antimicrobial factors to act synergistically with the carbapenem carrier.

     

Miniaturized surface engineered technologies for multiplex biosensing devices

The demand for quick, accurate, and affordable point-of-care (POC) devices increases with the advancement in the dimensions of nanotechnology and digital interfaces (Internet of Things). The future of diagnostic requires the platform which can provide us the following benefits i. e., on-site detection, qualitative as well as quantitative analysis, easy to use, portable, low sample requirement, cost-effective, and have multiplexing proficiency. Multiplex biosensing platforms (MBPs) have the above following advantages so are going to be mostly used in various healthcare applications in near future. MBPs have the potential to fulfill the ‘ASSURED’ criteria specified by the World Health Organization (WHO) for remote-limited settings. This review paper focuses on miniaturized platforms that have multiplexing benefits for the bioanalysis of different clinical samples related to various healthcare applications. In addition to this, screening of pesticides, antibiotics, and hazardous metal ions with these surface-engineered devices has also been accounted in food and environmental samples. Some of the advanced techniques including microfluidics (Lab-on-a-chip), wearable smart devices, and CRISPR/Cas system for multiplexing applications are briefly described here. Furthermore, various needs, challenges, and prospects in commercializing these multiplexed surface-engineered devices have been discussed in this review.     

Eco‐friendly,ultrasound‐assisted,and facile synthesis of one‐pot multicomponent reaction of acridine‐1,8(2H,5H)‐diones in an aqueous solvent

A one‐pot, multistep synthesis of acridine‐1,8(2H,5H)‐diones ( 4a–m ) was achieved by three‐component reaction of dimedone ( 1 ) with an aromatic aldehyde ( 2a–m ) and an ammonium acetate ( 3 ) using water as a green solvent without any catalyst and a simple, easily handled, and ultrasonic technique as well as conventional method.     

Novel Tripod Amphiphiles for Membrane Protein Analysis

Integral membrane proteins play central roles in controlling the flow of information and molecules across membranes. Our understanding of membrane protein structures and functions, however, is seriously limited, mainly due to difficulties in handling and analysing these proteins in aqueous solution. The use of a detergent or other amphipathic agents is required to overcome the intrinsic incompatibility between the large lipophilic surfaces displayed by the membrane proteins in their native forms and the polar solvent molecules. Here, we introduce new tripod amphiphiles displaying favourable behaviours toward several membrane protein systems, leading to an enhanced protein solubilisation and stabilisation compared to both conventional detergents and previously described tripod amphiphiles.     

Structural Insights on Mycobacterium tuberculosis Thiazole Synthase—A Molecular Dynamics/Docking Approach

Tuberculosis (TB), an epidemic disease, affects the world with death rate of two million people every year. The bacterium Mycobacterium tuberculosis was found to be a more potent and disease-prolonged bacterium among the world due to multi-drug resistance. Emergence of new drug targets is needed to overcome the bacterial resistance that leads to control epidemic tuberculosis. The pathway thiamine biosynthesis was targeting M. tuberculosis due to its role in intracellular growth of the bacterium. The screening of enzymes involved in thiamin biosynthesis showed novel target thiazole synthase (ThiG) involved in catalysis of rearrangement of 1-deoxy-d-xylulose 5-phosphate (DXP) to produce the thiazole phosphate moiety of thiamine. We carried out homology modeling for ThiG to understand the structure–function relationship, and the model was refined with MD simulations. The results showed that the model predicted with (α?+?β)₈-fold of synthase family proteins. Molecular docking of ThiG model with substrate DXP showed binding mode and key residues ARG46, ASN69, THR41, and LYS96 involved in the catalysis. First-line anti-tuberculosis drugs were docked with ThiG to identify the inhibition. The report showed the anti-tuberculosis drugs interact well with ThiG which may lead to block thiamin biosynthesis pathway.     

Exploring the Structural Insights on Human Laforin Mutation K87A in Lafora Disease—A Molecular Dynamics Study

Lafora disease (LD) is an autosomal recessive, progressive form of myoclonus epilepsy which affects worldwide. LD occurs mainly in countries like southern Europe, northern Africa, South India, and in the Middle East. LD occurs with its onset mainly in teenagers and leads to decline and death within 2 to 10 years. The genes EPM2A and EPM2B are commonly involved in 90 % of LD cases. EPM2A codes for protein laforin which contains an amino terminal carbohydrate binding module (CBM) belonging to the CBM20 family and a carboxy terminal dual specificity phosphatase domain. Mutations in laforin are found to abolish glycogen binding and have been reported in wet lab methods. In order to investigate on structural insights on laforin mutation K81A, we performed molecular dynamics (MD) simulation studies for native and mutant protein. MD simulation results showed loss of stability due to mutation K87A which confirmed the structural reason for conformational changes observed in laforin. The conformational change of mutant laforin was confirmed by analysis using root mean square deviation, root mean square fluctuation, solvent accessibility surface area, radius of gyration, hydrogen bond, and principle component analysis. Our results identified that the flexibility of K87A mutated laforin structure, with replacement of acidic amino acid to aliphatic amino acid in functional CBM domain, have more impact in abolishing glycogen binding that favors LD.     

Ruthenium(IV) pyrochlore oxides: Realization of novel electronic properties through substitution at A- and B-sites

We describe an exploratory investigation of the structure and electronic properties of new ruthenium(IV) pyrochlore oxides and their manganese-substituted derivatives. Our investigations have revealed several, hitherto unreported, electronic ground states for these materials: a metallic and Pauli paramagnetic state for BiPbRu₂O_6.5 that turns into a semiconducting ferromagnetic spin-glass state at 50 K for BiPbRuMnO_6.5; a metallic state that likely shows a charge density wave (CDW) instability at 50–225 K for Bi_1.50Zn_0.50Ru₂O_6.75 that is suppressed by manganese substitution in Bi_1.50Zn_0.50Ru_1.75Mn_0.25O_6.50; and a metallic ferromagnetic spin-glass like state for Pb₂Ru_1.75Mn_0.25O_6.15. The results indeed affirm the richness of the electronic properties of ruthenium-based metal oxides.