Fragment based drug design and diversity-oriented synthesis of carboxylic acid isosteres

Ferri, Martina; Alunno, Manuel; Greco, Francesco; Mammoli, Andrea; Saluti, Giorgio; Carotti, Andrea; Sardella, Roccaldo; Macchiarulo, Antonio; Camaioni, Emidio; Liscio, Paride

doi:10.1016/j.bmc.2020.115731

Cited by 8 publications

(11 citation statements)

References 30 publications

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“…According to the previous determinations of p Ka and log D values at pH 3 and 8 [21], the Sirius T3 produced highly accurate results (standard deviations were always below 5%).…”

Section: Introductionmentioning

confidence: 82%

“…All the reagents were of analytical grade. All the test fragments were synthesized in our laboratory, according to the procedures described in [21]. ACN (MeCN), methanol (MeOH), monobasic sodium phosphate (NaH 2 PO 4 ), dibasic sodium phosphate (Na 2 HPO 4 ), concentrated phosphoric acid (H 3 PO 4 ), n ‐octanol, n ‐butylamine, n ‐octylamine, and sodium nitrite (NaNO 2 ) were purchased from Merck Life Science S.r.l.…”

Section: Methodsmentioning

confidence: 99%

“…In particular, the apparatus was used to determine experimental log D values of our series of small molecules 1–16 (Table 1) by using potentiometric titrations. Details about the procedure are fully described elsewhere [21].…”

Section: Methodsmentioning

confidence: 99%

“…3D Coordinates of each compound were obtained as reported in the original synthetic work [21]. Briefly, fragments were built in all the tautomeric states of interest.…”

Section: Methodsmentioning

confidence: 99%

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Estimating the hydrophobicity extent of molecular fragments using reversed‐phase liquid chromatography

Carotti,

Varfaj,

Pruscini

et al. 2023

J of Separation Science

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A fast HPLC method was developed to study the hydrophobicity extent of pharmaceutically relevant molecular fragments. By this strategy, the reduced amount of sample available for physico‐chemical evaluations in early‐phase drug discovery programs does not represent a limiting factor. The sixteen acid fragments investigated were previously synthesized also determining potentiometrically their experimental log D values. For four fragments it was not possible to determine such property since their values were outside of the instrumental working range (2 < pKa < 12). An RP‐HPLC method was therefore optimized. For each scrutinized method, some derived chromatographic indices were calculated, and Pearson's correlation coefficient (r) allowed to select the so‐called “φ0 index” as the best correlating with the log D. The was fixed at 3.5 and a modification of some variables [organic modifier (methanol vs. ACN), stationary phase (octyl vs. octadecyl), presence/absence of the additives n‐octanol, n‐butylamine, and n‐octylamine], allowed to select the best correlation conditions, producing a r = 0.94 (p < 0.001). Importantly, the φ0 index enabled the estimation of log D values for four fragments which were unattainable by potentiometric titration. Moreover, a series of molecular descriptors were calculated to identify the chemical characteristics of the fragments explaining the obtained φ0. The number of hydrogen bond donors and the index of cohesive interaction correlated with the experimental data.

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“…According to the previous determinations of p Ka and log D values at pH 3 and 8 [21], the Sirius T3 produced highly accurate results (standard deviations were always below 5%).…”

Section: Introductionmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…3D Coordinates of each compound were obtained as reported in the original synthetic work [21]. Briefly, fragments were built in all the tautomeric states of interest.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Estimating the hydrophobicity extent of molecular fragments using reversed‐phase liquid chromatography

Carotti,

Varfaj,

Pruscini

et al. 2023

J of Separation Science

Self Cite

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“…Academic initiatives have also proposed libraries of fragments built by maximizing structural or shape diversity, such as libraries developed based on diversityoriented synthetic (DOS) strategy (Kidd et al, 2018). The diverse fragment libraries can serve different purposes, ranging from being a tool to study ligand-protein interactions or to facilitate bioisosteric replacement (Heidrich et al, 2019;Ferri et al, 2020) to the screening collection applicable to a wide variety of target proteins, such as the Diamond iNext Poised library of the Structural Genomics Consortium (DSiP) and the F2X chemical library, which both have been designed taking into account the diversity of chemical structures (Cox et al, 2016;Wollenhaupt et al, 2020). The diversity of chemical structures, however, does not presage the ability to provide hits for different proteins, as structurally dissimilar fragments may exhibit the same biological activity.…”

Section: Introductionmentioning

confidence: 99%

Mining the Protein Data Bank to inspire fragment library design

Imbernon

Chiesa²,

Kellenberger³

2023

Front. Chem.

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The fragment approach has emerged as a method of choice for drug design, as it allows difficult therapeutic targets to be addressed. Success lies in the choice of the screened chemical library and the biophysical screening method, and also in the quality of the selected fragment and structural information used to develop a drug-like ligand. It has recently been proposed that promiscuous compounds, i.e., those that bind to several proteins, present an advantage for the fragment approach because they are likely to give frequent hits in screening. In this study, we searched the Protein Data Bank for fragments with multiple binding modes and targeting different sites. We identified 203 fragments represented by 90 scaffolds, some of which are not or hardly present in commercial fragment libraries. By contrast to other available fragment libraries, the studied set is enriched in fragments with a marked three-dimensional character (download at 10.5281/zenodo.7554649).

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Palladium‐Catalyzed Enantioselective Intramolecular Heck Carbonylation Reactions: Asymmetric Synthesis of 2‐Oxindole Ynones and Carboxylic Acids

Zhang

Xiong

Guo

et al. 2021

Chemistry A European J

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Herein, we report a Pd-catalyzed enantioselective domino Heck carbonylation reaction of o-iodoacrylanilides with terminal alkynes and water as the nucleophiles, affording a diversity of β-carbonylated 2-oxindole derivatives bearing a 3,3-disubstituted all-carbon quaternary stereocenter, in high yields (55-99 %) with good to excellent enantioselectivities (up to 99 % ee). The synthetic utilities of the protocol were demonstrated in the gram-scale synthesis of 2-oxindolederived ynone 3 ea and carboxylic acid 4 a, as well as the facile synthesis of chiral 2-oxindoles with a pyrazole or isoxazole moiety.

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Fragment based drug design and diversity-oriented synthesis of carboxylic acid isosteres

Cited by 8 publications

References 30 publications

Estimating the hydrophobicity extent of molecular fragments using reversed‐phase liquid chromatography

Estimating the hydrophobicity extent of molecular fragments using reversed‐phase liquid chromatography

Mining the Protein Data Bank to inspire fragment library design

Palladium‐Catalyzed Enantioselective Intramolecular Heck Carbonylation Reactions: Asymmetric Synthesis of 2‐Oxindole Ynones and Carboxylic Acids

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