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Interactive Molecular Model Assembly with 3D Printing
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Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs
Emma Danelius1, Vasanthanathan Poongavanam1, Stefan Peintner1
1Department of Chemistry-BMC, Uppsala University, 75123, Uppsala, Sweden.
Chemistry (Weinheim an Der Bergstrasse, Germany)
|February 7, 2020
Summary
Drugs beyond the rule of 5 (bRo5) act as molecular chameleons, adapting their flexibility and conformation. This adaptability balances solubility, permeability, and target binding for oral drug design.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Drug Discovery
Background:
- Drugs
- beyond the rule of 5
- (bRo5) present challenges in balancing aqueous solubility, cell permeability, and target binding.
- Previous evidence for molecular chameleonicity was limited to cyclosporine A.
Purpose of the Study:
- To investigate whether non-peptidic, macrocyclic drugs exhibit molecular chameleonicity.
- To explore the conformational behavior of these drugs in different environments.
- To correlate drug properties with passive cell permeability and theoretical models.
Main Methods:
- Conformational analysis of roxithromycin, telithromycin, spiramycin, and rifampicin in polar and apolar solvents.
- Assessment of drug flexibility and conformational ensembles.
- Correlation of passive cell permeability with 3D polar surface area.
Main Results:
- Non-peptidic macrocyclic drugs (roxithromycin, telithromycin, spiramycin) demonstrate molecular chameleonicity.
- These drugs exhibit environment-dependent conformational changes, balancing permeability and solubility.
- Drug flexibility facilitates binding to diverse species-specific targets.
- Permeability correlates with 3D polar surface area, supporting existing theoretical models.
Conclusions:
- Molecular chameleonicity is a key property for orally administered bRo5 drugs.
- Incorporating chameleonicity in drug design can overcome limitations of bRo5 compounds.
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