| 1. |
- Aaldering, L. J., et al.
(författare)
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Development of an Efficient G-Quadruplex-Stabilised Thrombin-Binding Aptamer Containing a Three-Carbon Spacer Molecule
- 2017
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Ingår i: ChemBioChem. - : Wiley-VCH Verlag. - 1439-4227 .- 1439-7633. ; 18:8, s. 755-763
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Tidskriftsartikel (refereegranskat)abstract
- The thrombin-binding aptamer (TBA), which shows anticoagulant properties, is one of the most studied G-quadruplex-forming aptamers. In this study, we investigated the impact of different chemical modifications such as a three-carbon spacer (spacer-C3), unlocked nucleic acid (UNA) and 3′-amino-modified UNA (amino-UNA) on the structural dynamics and stability of TBA. All three modifications were incorporated at three different loop positions (T3, T7, T12) of the TBA G-quadruplex structure to result in a series of TBA variants and their stability was studied by thermal denaturation; folding was studied by circular dichroism spectroscopy and thrombin clotting time. The results showed that spacer-C3 introduction at the T7 loop position (TBA-SP7) significantly improved stability and thrombin clotting time while maintaining a similar binding affinity as TBA to thrombin. Detailed molecular modelling experiments provided novel insights into the experimental observations, further supporting the efficacy of TBA-SP7. The results of this study could provide valuable information for future designs of TBA analogues with superior thrombin inhibition properties.
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| 2. |
- Natarajan Arul, Murugan, et al.
(författare)
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Recent Advancements in Computing Reliable Binding Free Energies in Drug Discovery Projects
- 2019
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Ingår i: Structural Bioinformatics. - Cham : Springer. - 9783030052812 - 9783030052829 ; , s. 221-246
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Bokkapitel (refereegranskat)abstract
- In recent times, our healthcare system is being challenged by many drug-resistant microorganisms and ageing-associated diseases for which we do not have any drugs or drugs with poor therapeutic profile. With pharmaceutical technological advancements, increasing computational power and growth of related biomedical fields, there have been dramatic increase in the number of drugs approved in general, but still way behind in drug discovery for certain class of diseases. Now, we have access to bigger genomics database, better biophysical methods, and knowledge about chemical space with which we should be able to easily explore and predict synthetically feasible compounds for the lead optimization process. In this chapter, we discuss the limitations and highlights of currently available computational methods used for protein–ligand binding affinities estimation and this includes force-field, ab initio electronic structure theory and machine learning approaches. Since the electronic structure-based approach cannot be applied to systems of larger length scale, the free energy methods based on this employ certain approximations, and these have been discussed in detail in this chapter. Recently, the methods based on electronic structure theory and machine learning approaches also are successfully being used to compute protein–ligand binding affinities and other pharmacokinetic and pharmacodynamic properties and so have greater potential to take forward computer-aided drug discovery to newer heights.
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| 3. |
- Zhang, J., et al.
(författare)
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Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant
- 2018
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society. - 0022-2623 .- 1520-4804. ; 61:22, s. 9976-9999
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Tidskriftsartikel (refereegranskat)abstract
- Due to the emergence of highly pathogenic and oseltamivir-resistant influenza viruses, there is an urgent need to develop new anti-influenza agents. Herein, five subseries of oseltamivir derivatives were designed and synthesized to improve their activity toward drug-resistant viral strains by further exploiting the 150-cavity in the neuraminidases (NAs). The bioassay results showed that compound 21h exhibited antiviral activities similar to or better than those of oseltamivir carboxylate (OSC) against H5N1, H5N2, H5N6, and H5N8. Besides, 21h was 5- to 86-fold more potent than OSC toward N1, N8, and N1-H274Y mutant NAs in the inhibitory assays. Computational studies provided a plausible rationale for the high potency of 21h against group-1 and N1-H274Y NAs. In addition, 21h demonstrated acceptable oral bioavailability, low acute toxicity, potent antiviral activity in vivo, and high metabolic stability. Overall, the above excellent profiles make 21h a promising drug candidate for the treatment of influenza virus infection.
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