Structural biology in antiviral drug discovery

Bassetto, Marcella; Massarotti, Alberto; Coluccia, Antonio; Brancale, Andrea

doi:10.1016/j.coph.2016.08.014

Cited by 12 publications

(5 citation statements)

References 62 publications

(68 reference statements)

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“…Furthermore, crystallographic and other structural data can be very useful in the implementation of virtual screening technology applied to high-throughput screening of large libraries of compounds. 254…”

Section: Structural Biology Studies Help To Elucidate Resistance Mechanisms and Conduct Precise Drug Designmentioning

confidence: 99%

Medicinal chemistry strategies for discovering antivirals effective against drug-resistant viruses

et al. 2021

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Section: Structural Biology Studies Help To Elucidate Resistance Mechanisms and Conduct Precise Drug Designmentioning

confidence: 99%

Medicinal chemistry strategies for discovering antivirals effective against drug-resistant viruses

et al. 2021

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“…Therefore, a molecular docking study was performed to identify possible molecular interactions and important chemical features of the CHVB compounds with their main viral target protein (nsP1, see Supporting Information). 29 In Vitro Absorption, Distribution, Metabolism, and Excretion (ADME) Profiling. The objective of discovering new analogues with improved antiviral potency over 1b…”

Section: Hnmentioning

confidence: 99%

Design, Synthesis, and Lead Optimisation of CHVB Series Analogues as Potent Small Molecule Inhibitors of Chikungunya Virus

Battisti

Moesslacher

Abdelnabi

et al. 2022

Preprint

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The worldwide re-emerge of the Chikungunya virus (CHIKV), the high morbidity associated with it, and the lack of an available vaccine or antiviral treatment make the development of a potent CHIKV-inhibitor highly desirable. Therefore, an extensive lead optimisation was performed based on the previously reported CHVB compound 1b and the reported synthesis route was optimised - improving the overall yield in remarkable shorter synthesis and work-up time. 100 CHVB analogues were designed, synthesised, and investigated for their antiviral activity, physiochemistry, and toxicological profile. An extensive structure-activity relationship study (SAR) was performed, which focused mainly on the combination of scaffold changes and revealed the key chemical features for a high anti-CHIKV inhibition. Further, to investigate the druggability of the compound series, a thorough ADMET investigation was carried out: the compounds were screened for their aqueous solubility, lipophilicity, their toxicity in CaCo-2 cells, and possible hERG channel interactions. Additionally, 55 analogues were assessed for their metabolic stability in human liver microsomes (HLMs) which led to a structure-metabolism relationship study (SMR). The compounds showed an excellent safety profile, favourable physicochemical characteristics, and the required metabolic stability. A cross-resistance study confirmed the viral capping machinery (nsP1) to be the viral target of these second-generation CHVB compounds. This study identified five compounds (31b, 31d, 32d, 34, and 35d) as potent, safe, and stable lead compounds for further development as selective CHIKV inhibitors - with 32d as the most promising candidate. Finally, the collected insight led to a successful scaffold hop (64b) for future antiviral research studies.

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“…To date, about 10,837 virus-related structures are available in the PDB, more than 77% of them containing viruses only. Most virus structures in the PDB (around 85%) have been determined using X-ray crystallography (PDB: https://www.wwpdb.org/; [44]) [45]. The abovementioned structures include not only proteins forming icosahedral capsids, proteins of cylindrical viruses, and different components of tailed phages, but also many virus enzymes as proteases, and RNA/DNA polymerases [41,43].…”

Section: Challenging Samples: Macromolecular Assemblies and Subunitsmentioning

confidence: 99%

Applications of X-ray Powder Diffraction in Protein Crystallography and Drug Screening

et al. 2020

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Providing fundamental information on intra/intermolecular interactions and physicochemical properties, the three-dimensional structural characterization of biological macromolecules is of extreme importance towards understanding their mechanism of action. Among other methods, X-ray powder diffraction (XRPD) has proved its applicability and efficiency in numerous studies of different materials. Owing to recent methodological advances, this method is now considered a respectable tool for identifying macromolecular phase transitions, quantitative analysis, and determining structural modifications of samples ranging from small organics to full-length proteins. An overview of the XRPD applications and recent improvements related to the study of challenging macromolecules and peptides toward structure-based drug design is discussed. This review congregates recent studies in the field of drug formulation and delivery processes, as well as in polymorph identification and the effect of ligands and environmental conditions upon crystal characteristics. These studies further manifest the efficiency of protein XRPD for quick and accurate preliminary structural characterization.

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Structural biology in antiviral drug discovery

Abstract: Structural biology has emerged during the last thirty years as a powerful tool for rational drug discovery.

Cited by 12 publications

References 62 publications

Medicinal chemistry strategies for discovering antivirals effective against drug-resistant viruses

Medicinal chemistry strategies for discovering antivirals effective against drug-resistant viruses

Design, Synthesis, and Lead Optimisation of CHVB Series Analogues as Potent Small Molecule Inhibitors of Chikungunya Virus

Applications of X-ray Powder Diffraction in Protein Crystallography and Drug Screening

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