• Non ci sono risultati.

Physico-chemical characterization, permeability and molecular dynamics simulations of two series of structurally related macrocycles

N/A
N/A
Protected

Academic year: 2021

Condividi "Physico-chemical characterization, permeability and molecular dynamics simulations of two series of structurally related macrocycles"

Copied!
2
0
0

Testo completo

(1)

21 July 2021

AperTO - Archivio Istituzionale Open Access dell'Università di Torino

Original Citation:

Physico-chemical characterization, permeability and molecular dynamics simulations of two series of structurally related macrocycles

Terms of use: Open Access

(Article begins on next page)

Anyone can freely access the full text of works made available as "Open Access". Works made available under a Creative Commons license can be used according to the terms and conditions of said license. Use of all other works requires consent of the right holder (author or publisher) if not exempted from copyright protection by the applicable law. Availability:

This is the author's manuscript

(2)

Physico-chemical characterization, permeability and molecular dynamics simulations of two series of structurally related macrocycles

Maura Vallaro, Maria del Pilar Camacho Leal, Giuseppe Ermondi and Giulia Caron

Molecular Biotechnology and Health Sciences Dept., Università degli Studi di Torino, via Quarello 15, 10135 Torino, Italy.

Email: giulia.caron@unito.it; Web site: www.cassmedchem.unito.it

Aim

To characterize the physico-chemical profile and permeability of two series of macrocycles (MCs): temsirolimus, everolimus (ascomycin class) and rifabutin, rifampicin, rifapentine, rifamixin (ansamycin class) and to predict the influence of the environment on low energy conformations.

Methods

Experimental and in silico tools were used.

pKa values were calculated with MoKa v.2.5.4. (www.moldiscovery.com).

Four chromatographic lipophilicity indexes were measured. The following stationary phases were used: a) Supelcosil TM LC-ABZ alkylamide column; b) PLRP-S polymeric reversed phase column; c) ZIC-HILIC column (sulfoalkylbetaine phase on a silica gel support) and d) ZIC-cHILIC column (phosphorylcholine phase covalently attached to porous silica). The mobile phase consisted of 20 mM ammonium acetate buffer at pH 7.0 and acetonitrile in varying proportions.

Permeability was measured with an MDCK cell-based permeability assay.

Molecular Dynamics (MD) were performed using AMBER (ver. 14, www.amber.org) with standard protocols.

Results

We determined ionization constants (pKa), logarithm of the retention factors (log k), permeability coefficients (Papp). Temsirolimus and everolimus are neutral at pH = 7.0 and have similar lipophilicity in the four investigated systems. Conversely, the ionization profiles of ansamycins are complex and markedly influence lipophilicity expressed as the logarithm of the retention factors and permeability. MD simulations provide insights in the evaluation of low energy conformational ensembles of macrocycles in apolar (chromatographic systems a) and b)) and polar (chromatographic systems c) and d)) media.

Conclusion

The determination of the physico-chemical profile of MCs requires a wise application of the lessons learnt from small organic molecules but also additional specific tools. This is due to the MCs conformational variability, which is influenced by different bioenvironments in a larger extent than small organic drugs.

Riferimenti

Documenti correlati

Molecular dynamics simulations were used in this work to probe the structural stability and the dynamics of engi- neered mutants of transthyretin (TTR), i.e., the double

14 Georgetown University Center on Education and the Workforce analysis of US Bureau of Economic Analysis, Interactive Access to Industry Economic Accounts Data: GDP by

Overall, this thesis explores various aspects favouring the formation of misfolded and/or (un)folded protein species, ranging from dissociation of an homotetramer of

The dominant medical model employed in contemporary medical research and clinical practice is grounded an empiricist theory of language. Disea- ses are conceived as

Also the morphology of the skin shows some adaptations to the arid environment and previous microscopic analysis of the epidermis in this species has shown the presence of a

menzionata giustiziabilità del parametro, la portata del sistema dei controlli, prestando attenzione al ruolo della Corte dei conti nel ciclo della quantifica- zione degli

Altri gruppi consistenti di patrimonio si aprivano nella parte superiore del Campo Giavesu in direzione di Cheremule e di Thiesi. La natura paludosa del fondo valle e