The Block Relevance (BR) analysis supports the dominating effect of solutes hydrogen bond acidity on ΔlogPoct–tol

Ermondi, Giuseppe; Visconti, Alessia; Esposito, Roberto

doi:10.1016/j.ejps.2013.12.007

Cited by 27 publications

(48 citation statements)

References 21 publications

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“…BR analysis supports this expectancy (Fig. 2C) showing that ∆log Poct-tol is mostly influenced by HBD solutes' property (red block, positive sign) and it is poorly influenced by steric descriptors (green block, negative sign) [14]. The presence of IMHBs thus produces low ∆log Poct-tol values.…”

Section: Going Beyond Octanol/water and Combining Log Pssupporting

confidence: 67%

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Log P as a tool in intramolecular hydrogen bond considerations

Caron

Vallaro

2018

Drug Discovery Today: Technologies

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Intramolecular hydrogen bonding (IMHB) considerations are gaining relevance in drug discovery and a molecular descriptor which can predict very early the capacity of a compound to form IMHB is needed to speed up the optimization process of drug candidates. Although log P is largely used for optimization purposes, in this paper we firstly use the Block Relevance (BR) analysis to theoretically show how log P is not a convenient choice to assess IMHB properties of candidates. Then we discuss the limits of log P and introduce Δlog P, i.e. the difference between log P and log P (the logarithm of the partition coefficient in the toluene/water system). Finally, we provided some examples also including bRo5 protease inhibitors, to clarify how to interpret Δlog P values.

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Section: Going Beyond Octanol/water and Combining Log Pssupporting

confidence: 67%

“…Therefore, the formation of an IMHB which mostly reduces HDB properties exposure does not have a strong impact on log Poct. [13], B) log Ptol [13] and C) ∆logPoct-tol [14].…”

Section: Figure 1 a Molecule With A Hydrogen Donor Group Hbd (D-h) Amentioning

confidence: 99%

Log P as a tool in intramolecular hydrogen bond considerations

Caron

Vallaro

2018

Drug Discovery Today: Technologies

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“…63 In summary, these include a) Δlog P oct−tol , that is, the difference between log P oct and log P tol (i.e., the logarithm of the partition coefficient P in the toluene/water system), 64 Δlog P oct−tol is a clean descriptor of exposed HBD properties. 68 The presence of IMHBs produces low Δlog P oct−tol values. When a compound has a single HBD group (and at least one HBA), the compound has high propensity to form IMHBs if Δlog P oct-tol is close to 0.…”

Section: Quantum/molecular Mechanics-based Toolsmentioning

confidence: 99%

“…Δlog P oct−tol is a clean descriptor of exposed HBD properties . The presence of IMHBs produces low Δlog P oct−tol values.…”

Section: Which Tactics To Use When Including Imhb In Drug Design?mentioning

confidence: 99%

Intramolecular hydrogen bonding: An opportunity for improved design in medicinal chemistry

Caron

Kihlberg

2019

Medicinal Research Reviews

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Recent literature shows that intramolecular hydrogen bond (IMHB) formation can positively impact upon the triad of permeability, solubility, and potency of drugs and candidates. IMHB modulation can be applied to compounds in any chemical space as a means for discovering drug candidates with both acceptable potency and absorption, distribution, metabolism, and excretion‐Tox profiles. Integrating IMHB formation in design of drugs is, therefore, an exciting and timely challenge for modern medicinal chemistry. In this review, we first provide some background about IMHBs from the medicinal chemist's point of view and highlight some IMHB‐associated misconceptions. Second, we propose a classification of IMHBs for drug discovery purposes, review the most common in silico tactics to include IMHBs in lead optimization and list some experimental physicochemical descriptors, which quantify the propensity of compounds to form IMHBs. By focusing on the compounds size and the number of IMHBs that can potentially be formed, we also outline the major difficulties encountered when designing compounds based on the inclusion of IMHBs. Finally, we discuss recent case studies illustrating the application of IMHB to optimize cell permeability and physicochemical properties of small molecules, cyclic peptides and macrocycles.

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“…To provide an alternative tool to Abraham's equations, we have designed and implemented a chemoinformatic strategy named Block Relevance (BR) analysis [5] which affords an interpretation "at a glance" of QSPRs models based on a selected pool of descriptors and a Partial Least Square (PLS) algorithm. To fully understand BR analysis and thus its relevance in property-based drug design, we have briefly reviewed [6,7] some basic concepts of QSPR.…”

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confidence: 99%