P-13: Virtual Screening of an Anthracyclines Combinatorial Library Against DNA Topoisomerase II, Alpha Isozyme
Objective: Anthracyclines are a class of antineoplastic drugs used in cancer therapy. Anthracyclines interact with DNA by intercalation and inhibition of macromolecular biosynthesis and bind DNA topoisomerase II stopping the process of replication. This paper is a computational approach to identify and compare the binding affinity of a combinatorial library for DNA topoisomerase II, alpha isozyme. Materials and Methods: Based on two similar scaffold molecules it was build a virtual combinatorial library of possible derivatives. One scaffold molecule is common to daunorubicin (DNM), doxorubicin (DOX) and epirubicin (EPI) and another one is for idarubicin (IDA); valrubicin was excluded due its limited therapeutic applications. The combinatorial library was build with MarvinSketch 5.3.6, 2010, ChemAxon (http://www.chemaxon.com) imposing, alternatively, two sites of variability for each scaffold and replacing the methyl group attached at the carbonyl from the tetracene-5,12-dione backbone, respectively replacing the methyl group attached at the tetrahy<font><font>drop</font></font>yran ring with Markush structures. As Markush structures were used structural motifs, frequently found in antimetabolite and antineoplastic drugs (cyclophosphamide, mechlorethamine, uramustine, melphalan, lomustine, streptozotocin, busulfan, procarbazine, mercaptopurine, thioguanine, methotrexate, pemetrexed, raltitrexed). Prior to virtual screening, the combinatorial library was checked for “drug-likeness” using FAF-Drugs, ADME-Tox web-based software (http://mobyle.rpbs.univ-paris-diderot.fr/cgi-bin/portal.py). As limits for “drug-likeness” metrics were imposed the maximal values of these indicators for anthracyclines: molecular weight (200.0 Da to 724.0 Da), hydrogen donors (0 to 6), hydrogen acceptors (0 to 14), flexible bonds (0 to 12), ring number (0 to 7), logP (-2.0 to 5.0), polar surface area (0.0 Å to 216.0 Å). Anthracyclines and the qualified virtual derivatives were used for virtual screening with PyRx 0.7 (http://pyrx.scripps.edu) against human DNA topoisomerase II, alpha isozyme – SWISS-MODEL homologue (http://swissmodel.expasy.org) for P11388. For docking it was used AutoDock Vina (http://vina.scripps.edu), ran on local machine under the PyRx 0.7 interface. Results: Markush enumerations build a combinatorial library consisting in 176 virtual derivates. ADME-Tox filtering, according imposed limits reduced the size of combinatorial library at 34 derivatives. Docking results shown that the binding affinity of anticancer anthracyclines varies between -3.9 kcal/mol and -7.5 kcal/mol. For virtual derivatives, binding affinity varies between -3.2 kcal/mol and -8.5 kcal/mol. Conclusion: Some virtual derivates require a lower energy to bind and block the topoisomerase, being better ligands than the anticancer anthracyclines. These derivates can be used as leads (“leading” compounds) in order to improve their ADME-Tox properties or can be prioritized to synthesis in order to use them for bioassays as possible antiproliferative agents.