Fragment‐Based Lead Discovery

Albert, Jeffrey S.

doi:10.1002/9780470584170.ch4

Cited by 3 publications

(4 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A LE of 0.3 is generally considered as a minimum LE value desired in a drug candidate . For our analysis, we chose to use a LE ≥ 0.25 cut‐off to represent compounds with high LE, and found 14 ligands in our dataset that meet this criterion.…”

Section: Resultsmentioning

confidence: 99%

Applying conformational selection theory to improve crossdocking efficiency in 3‐phosphoinositide dependent protein kinase‐1

2013

View full text Add to dashboard Cite

The emerging picture of biomolecular recognition is that of conformational selection followed by induced-fit. Conformational selection theory states that binding partners exist in various conformations in solution, with binding involving a "selection" between complementary conformers. In this study, we devise a docking protocol that mimics conformational selection in protein-ligand binding and demonstrate that it significantly enhances crossdocking accuracy over Glide's flexible docking protocol, which is widely used in the pharmaceutical industry. Our protocol uses a pregenerated conformational ensemble to simulate ligand flexibility. The ensemble was generated by thorough conformational sampling coupled with conformer minimization. The generated conformers were then rigidly docked in the active site of the protein along with a postdocking minimization step that allows limited induced fit effects to be modeled for the ligand. We illustrate the improved performance of our protocol through crossdocking of 31 ligands to cocomplexed proteins of the kinase 3-phosphoinositide dependent protein kinase-1 extracted from the crystal structures 1H1W (ATP bound), 1OKY (staurosporine bound) and 3QD0 (bound to a potent inhibitor). Consistent with conformational selection theory, the performance of our protocol was the best for crossdocking to the cognate protein bound to the natural ligand, ATP.

show abstract

Section: Resultsmentioning

confidence: 99%

Applying conformational selection theory to improve crossdocking efficiency in 3‐phosphoinositide dependent protein kinase‐1

2013

View full text Add to dashboard Cite

show abstract

“…Justification for this exclusion may be based upon accepted wisdom, derived from personal experience (e.g., see Muegge and co-workers, Beck and co-workers, and discussions on internet forums, including the well-regarded “In the Pipeline” , ), or based on a well-established (if only potential) toxic liability associated solely with the aromatic nitro and its propensity for formation of an aryl nitrenium ion, which can bind to DNA . In additional examples of this general dismissal of the nitro group from the drug-like space, the nitro was one of the groups eliminated prior to the studies leading to Baell’s identification of the range of pan-assay interference compounds; likewise, any structures containing a nitro are explicitly excluded by Rankovic and Morphy as being acceptable for use in fragment-based lead discovery.…”

Section: Introductionmentioning

confidence: 99%

The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB₁ Receptor Positive Allosteric Modulators

et al. 2019

View full text Add to dashboard Cite

The first generation of CB 1 positive allosteric modulators (PAMs; e.g., ZCZ011) featured a 3-nitroalkyl-2-phenyl-indole structure. Although a small number of drugs include the nitro group, it is generally not regarded as being "drug-like", and this is particularly true for aliphatic nitro groups. There are very few case studies where an appropriate bioisostere replaced a nitro group that had a direct role in binding. This may be indicative of the difficulty of replicating its binding interactions. Herein we report the design and synthesis of ligands targeting the allosteric binding site on the CB 1 cannabinoid receptor, in which a CF 3 group successfully replaced the aliphatic NO 2 . In general, the CF 3 -bearing compounds were more potent than their NO 2 equivalents and also showed improved in vitro metabolic stability. The CF 3 -analogue (1) with the best balance of properties was selected for further

show abstract

“…Fragment-based ligand screening (FBLS) has emerged as a powerful tool to assess the druggability of proteins 12 13 . Besides the identification of ligands for a known binding site, a fragment-based screen can also reveal unique binding sites that are capable to interact with small molecule ligands.…”

mentioning

confidence: 99%

“…This technique entails the use of molecules of low molecular weight and chemical complexity to probe for areas that are energetically favourable for ligand binding 14 15 . The propensity of fragment molecules to interact with a protein is indicative of whether it can accommodate a molecule with drug-like properties 13 . FBLS has benefited in particular from the use of NMR spectroscopy for highly sensitive detection of interactions between ligand and protein, even at millimolar affinities 16 17 .…”

mentioning

confidence: 99%

Small Molecules Antagonise the MIA-Fibronectin Interaction in Malignant Melanoma

Yip

Zhong

Seibel

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Melanoma inhibitory activity (MIA), an extracellular protein highly expressed by malignant melanoma cells, plays an important functional role in melanoma development, progression, and metastasis. After its secretion, MIA directly interacts with extracellular matrix proteins, such as fibronectin (FN). By this mechanism, MIA actively facilitates focal cell detachment from surrounding structures and strongly promotes tumour cell invasion and migration. Hence, the molecular understanding of MIA’s function provides a promising target for the development of new strategies in malignant melanoma therapy. Here, we describe for the first time the discovery of small molecules that are able to disrupt the MIA-FN complex by selectively binding to a new druggable pocket, which we could identify on MIA by structural analysis and fragment-based screening. Our findings may inspire novel drug discovery efforts aiming at a therapeutically effective treatment of melanoma by targeting MIA.

show abstract

Fragment‐Based Lead Discovery

Cited by 3 publications

References 74 publications

Applying conformational selection theory to improve crossdocking efficiency in 3‐phosphoinositide dependent protein kinase‐1

Applying conformational selection theory to improve crossdocking efficiency in 3‐phosphoinositide dependent protein kinase‐1

The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB₁ Receptor Positive Allosteric Modulators

Small Molecules Antagonise the MIA-Fibronectin Interaction in Malignant Melanoma

Contact Info

Product

Resources

About

Fragment‐Based Lead Discovery

Cited by 3 publications

References 74 publications

Applying conformational selection theory to improve crossdocking efficiency in 3‐phosphoinositide dependent protein kinase‐1

Applying conformational selection theory to improve crossdocking efficiency in 3‐phosphoinositide dependent protein kinase‐1

The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB1 Receptor Positive Allosteric Modulators

Small Molecules Antagonise the MIA-Fibronectin Interaction in Malignant Melanoma

Contact Info

Product

Resources

About

The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB₁ Receptor Positive Allosteric Modulators