Drug discovery beyond the rule of 5 - Opportunities and challenges

Doak, B.C.; Kihlberg, Jan

doi:10.1080/17460441.2017.1264385

Cited by 83 publications

(71 citation statements)

References 21 publications

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“…Based on Table 2, LogP of GC2 and GC3 were 5.18 and 6.14 respectively, as predicted by the software (DS 2.5), and thus, they were categorized as having "poor" drug-like properties. Lipiski et al (2012) [30] predicted that poor absorption or permeation is more likely once logP is greater than five [31,32]. In this study, GC2 and GC3 were dissolved in a slightly higher concentration of DMSO (2.5%), due to low solubility and precipitation that might have occurred when the MES buffer was added.…”

Section: Binding Interaction Of the Isolated Compound From Garcinia Cmentioning

confidence: 90%

Anti-Neuraminidase Bioactives from Manggis Hutan (Garcinia celebica L.) Leaves: Partial Purification and Molecular Characterization

et al. 2020

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The neuraminidase enzyme (NA) from the influenza virus is responsible for the proliferation and infections of the virus progeny, prompting several efforts to discover and optimize effective neuraminidase inhibitors. The main aim of this study is to discover a new potential neuraminidase inhibitor that comes from Garcinia celebica leaves (GCL). The bioassay-guided isolation method was performed to obtain lead compounds. The binding interaction of the isolated compounds was predicted by using molecular docking studies. Friedeline (GC1, logP > 5.0), two lanastone derivatives (methyl-3α,23-dihydroxy-17,14-friedolanstan-8,14,24-trien-26-oat (GC2) and 24E-3a,9,23-trihydroxy-17,14-friedolanostan-14,24-dien-26-oate (GC3) with LogP > 5.0) and catechin (GC4, LogP = 1.4) were identified. The inhibitory potency of these four compounds on NA from C. perfringens and H1N1 was found to be as follows: GC4 > GC2 > GC3 > GC1. All compounds exhibited higher inhibitory activity towards C. perfringens NA compared to H1N1 NA. From the molecular docking results, GC4 favorably docked and interacted with Arg118, Arg371, Arg292, Glu276 and Trp178 residues, whilst GC2 interacted with Arg118, Arg371, Arg292, Ile222, Arg224 and Ser246. GC3 interacted with Tyr406 only. GC4 had potent NA inhibition with free energy of binding of −12 kcal/mol. In the enzyme inhibition study, GC4 showed the highest activity with an IC50 of 60.3 µM and 91.0 µM for C. perfringens NA and H1N1 NA—respectively.

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Section: Binding Interaction Of the Isolated Compound From Garcinia Cmentioning

confidence: 90%

Anti-Neuraminidase Bioactives from Manggis Hutan (Garcinia celebica L.) Leaves: Partial Purification and Molecular Characterization

et al. 2020

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“…There is significant current interest around the use of cyclic peptide scaffolds in drug discovery, especially for early stage hit discovery against intractable targets [37,38]. There is a growing body of evidence in the literature that supports the drive towards these molecules, which do not necessary fit in with conventional dogma in drug discovery and development [39,40]. The SICLOPPS methodology detailed here is one of a handful of techniques available for the generation of macrocycle libraries of hundreds of millions of members, and is arguably one of the simplest to adopt, and most flexible methods for library generation.…”

Section: Discussionmentioning

confidence: 99%

SICLOPPS cyclic peptide libraries in drug discovery

Tavassoli

2017

Current Opinion in Chemical Biology

107

103

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Cyclic peptide libraries have demonstrated significant potential when employed against challenging targets such as protein-protein interactions. While a variety of methods for library generation exist, genetically encoded libraries hold several advantages over their chemically synthesized counterparts; they are more readily accessible and allow straightforward hit deconvolution. One method for the intracellular generation of such libraries is split-intein circular ligation of peptides and proteins (SICLOPPS). Here we detail and discuss the deployment of SICLOPPS libraries for the identification of cyclic peptide inhibitors of a variety of targets.

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“…A newer challenge now facing the medicinal chemists is the emergence of molecules developed beyond the drug‐likeness space to meet previously undrugable targets. This is in addition to the evolution of modern therapeutics such as peptide and protein‐based drugs and of drugs derived from natural origin with poor ADME‐Tox properties . To cope with this evolution, chemical modification and pharmaceutical technology applications are tackled for adjusting the PK properties.…”

Section: Introductionmentioning

confidence: 99%

Chemical structure modifications and nano‐technology applications for improving ADME‐Tox properties, a review

Farouk

Shamma

2019

Archiv der Pharmazie

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The chemical structure of a drug molecule affects its physicochemical properties and subsequent biological activities. Many pharmacologically active molecules fail to reach the market or have an inconvenient route of administration due to their chemical structure. This is especially important with the recent tendency to develop drug candidates beyond the drug-likeness space for addressing difficult targets such as protein-protein interfaces. The objective of this review is to discuss chemical and pharmaceutical approaches for circumventing structure-related problems and achieving acceptable ADME-Tox properties. The chemical structure-associated limitations are critically discussed. Chemical modifications and pharmaceutical technology applications for improving drug-likeness are illustrated. Attention is paid to modern therapeutic candidates and targets. In conclusion, chemical modifications as well as nanotechnology applications can be used effectively to enhance absorption, permeability, and selective distribution to a body compartment, to improve drug specificity, to limit off-target toxicity as well as to enhance stability and to protect against metabolism. The nano-technology-based solutions are relatively easier to develop over a new molecular entity, but adopting the chemical approach is more established in terms of safety, quality control, and regulatory assessment methods. K E Y W O R D Sblood-brain barrier, cancer tissue delivery, drug delivery, drug targeting, protein-protein interaction

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Drug discovery beyond the rule of 5 - Opportunities and challenges

Cited by 83 publications

References 21 publications

Anti-Neuraminidase Bioactives from Manggis Hutan (Garcinia celebica L.) Leaves: Partial Purification and Molecular Characterization

Anti-Neuraminidase Bioactives from Manggis Hutan (Garcinia celebica L.) Leaves: Partial Purification and Molecular Characterization

SICLOPPS cyclic peptide libraries in drug discovery

Chemical structure modifications and nano‐technology applications for improving ADME‐Tox properties, a review

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