Increasing the Potential of the Auristatin Cancer-Drug Family by Shifting the Conformational Equilibrium

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http://hdl.handle.net/10138/304573

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Sokka , I K , Ekholm , F S & Johansson , M P 2019 , ' Increasing the Potential of the Auristatin Cancer-Drug Family by Shifting the Conformational Equilibrium ' , Molecular Pharmaceutics , vol. 16 , no. 8 , pp. 3600-3608 . https://doi.org/10.1021/acs.molpharmaceut.9b00437

Title: Increasing the Potential of the Auristatin Cancer-Drug Family by Shifting the Conformational Equilibrium
Author: Sokka, Iris Katariina; Ekholm, Filip S.; Johansson, Mikael P.
Contributor: University of Helsinki, Department
University of Helsinki, Department of Chemistry
University of Helsinki, Helsinki Institute of Sustainability Science (HELSUS)
Date: 2019-08
Language: eng
Number of pages: 9
Belongs to series: Molecular Pharmaceutics
ISSN: 1543-8384
URI: http://hdl.handle.net/10138/304573
Abstract: Monomethyl auristatin E and monomethyl auristatin F are widely used cytotoxic agents in antibody-drug conjugates (ADCs), a group of promising cancer drugs. The ADCs specifically target cancer cells, releasing the auristatins inside, which results in the prevention of mitosis. The auristatins suffer from a potentially serious flaw, however. In solution, the molecules exist in an equal mixture of two conformers, cis and trans. Only the trans-isomer is biologically active and the isomerization process, i.e., the conversion of cis to trans is slow. This significantly diminishes the efficiency of the drugs and their corresponding ADCs, and perhaps more importantly, raises concerns over drug safety. The potency of the auristatins would be enhanced by decreasing the amount of the biologically inactive isomer, either by stabilizing the transisomer or destabilizing the cis-isomer. Here, we follow the computer-aided design strategy of shifting the conformational equilibrium and employ high-level quantum chemical modeling to identify promising candidates for improved auristatins. Coupled cluster calculations predict that a simple halogenation in the norephedrine/phenylalanine residues shifts the isomer equilibrium almost completely toward the active trans-conformation, due to enhanced intramolecular interactions specific to the active isomer.
Subject: 116 Chemical sciences
cytotoxicity
molecular modeling
computer-aided drug design
intramolecular interactions
quantum chemistry
drug development
ORBITAL COUPLED-CLUSTER
BINDING FREE-ENERGIES
ELECTRONIC-STRUCTURE
BASIS-SETS
CONJUGATES ADCS
MAGIC BULLETS
ANTIBODY
PROGRAM
CELL
EHRLICH,PAUL
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