Cancer has become one of leading causes of death around the globe, with female breast cancer as one of
the most prevalent. Among the multiple types of breast cancer (BC) identified to date, the triple-negative
(TN) subtype (lacking expression of estrogen and progesterone receptors and human epidermal growth
factor receptor 2) is associated with higher aggressiveness and poor prognosis [1]. TNBC lacks targeted
therapies and presents heterogeneous responses to treatment with traditional cisplatin-like drugs, in part
due to the development of multidrug resistance (MDR). TM34 is a Ruthenium-based compound that has
been suggested to be a more efficient and selective therapy than cisplatin [2]. More recently, new
derivatives of TM34 have been developed with increased selectivity by adding peptide sequences that are
recognized by receptor proteins from the FGFR family [3].
The main goal of this work is to study the interaction of several TM34 derivatives with a membrane model
(POPC) and to calculate their membrane crossing energy profiles that can be used to estimate the
membrane permeability coefficients. We used Molecular Dynamics simulations coupled with an
Umbrella-sampling scheme to obtain the potential of mean force profiles, which allowed the calculation
of the membrane permeability using the inhomogeneous solubility-diffusion model [4].

Acknowledgements: We acknowledge Fundação para a Ciência e Tecnologia (FCT) for funding through projects
UIDB/00100/2020 (CQE), UIDB/04046/2020 & UIDP/04046/2020 (BioISI), and PTDC/QUI-QIN/0146/2020. T.S.
Morais and M. Machuqueiro thank the CEECIND 2017 Initiative for projects CEECIND/00630/2017 and
CEECIND/02300/2017, respectively (acknowledging FCT, as well as POPH and FSE-European Social Fund).

[1] Rakha EA, Ellis IO. Triple-negative/basal-like breast cancer: review. Pathology. 2009;41: 40–47.
[2] Lin K, Zhao Z-Z, Bo H-B, Hao X-J, Wang J-Q. Applications of Ruthenium Complex in Tumor Diagnosis and Therapy.
Front Pharmacol. 2018;9: 1323.

[3] Machado JF, Machuqueiro M, Marques F, Robalo MP, Piedade MFM, Garcia MH, et al. Novel “ruthenium
cyclopentadienyl”--peptide conjugate complexes against human FGFR (+) breast cancer. Dalton Trans J Inorg Chem.
2020;49: 5974–5987.
[4] Dickson CJ, Hornak V, Pearlstein RA, Duca JS. Structure-Kinetic Relationships of Passive Membrane Permeation
from Multiscale Modeling. J Am Chem Soc. 2017;139: 442–452