1. Dynamic Docking Studies of Human TopoII Bound to Potential TopoII Inhibitors. To develop an ETO-based drug with specificity for cancer cells the sugar moiety of the drug has been previously replaced with a polyamine tail. Such inhibitors would be preferentially taken up by cancer cells thereby lessening off-target effects in noncancerous cells. We analyzed the activity of a series of ETO-polyamine hybrids toward human TopoIIα and IIβ. All of these compounds induce higher/comparable enzyme-mediated DNA cleavage than induced by ETO. Relative to the parent drug, the hybrid compounds displayed substantially higher activity toward TopoIIβ than IIα. In collaboration with Prof. Neil Osheroff, Vanderbilt University, we provided the basis for the enhanced specificity of polyamine derivatives of ETO to TopoIIβ. Our enzymology & modeling studies form the basis of a testable hypothesis for the design of future drugs with enhanced specificity toward a single isoform of human TopoII.
2. Classical and Smoothed Potential MD Simulations to Unravel Isoform Specificity in Targeting Human TopoII. Current clinical TopoII poisons are nonspecific with regard to TopoIIα and TopoIIβ. However, strong support has been provided by both cellular and in vivo studies that TopoIIβ is primarily responsible for processes that initiate the secondary leukemias associated with ETO treatment. Hence, TopoIIα-specific poisoning might help mitigate the side effects observed with nonspecific TopoII drugs. However, the rational design of TopoIIα selective inhibitors is difficult as the two isoforms share ~78% identity at the catalytic site. We reported that TopoIIα exhibits ~3-fold more drug-target residence time with ETO as compared to TopoIIβ. This may reduce the adverse effects of specific TopoIIα poisons. To clarify how to design TopoIIα specific drugs, we employed classical molecular dynamics (MD) simulations to comparatively analyze the interactions formed within the TopoII/DNA/ETO complex in both isoforms. We also used smoothed potential MD to estimate ETO dissociation kinetics from the two isoform complexes. These extensive simulations revealed stabilizing interactions of ETO with amino acid residues in TopoIIα, which are missing in TopoIIβ. This may explain the greater persistence of ETO-stabilized cleavage complexes formed with TopoIIα. The study provides a structural and kinetic rationale for the design of novel TopoIIα-specific drugs, which can stably engage these amino acid residues.
3. Dynamic Docking to Elucidate the Interactions of TopoII and a New Class of TopoII Inhibitors. Based on the previously reported hybrid TopoII inhibitors that merge key pharmacophoric elements of ETO and merbarone, the molecular entity was expanded by synthesizing sixteen additional hybrid derivatives. Dynamic docking studies were performed to identify the vital interactions stabilizing the hybrid TopoII inhibitors. Most of these new compounds exhibited good inhibitory activity and cytotoxicity in three cancer cell lines with an IC50 in the low μM range. Hence, understanding the key molecular features needed for the drug-like properties in this novel chemical series of TopoII targeting compounds will aid in developing the new structural motif as a potential TopoII poison.
Dissemination
Publications
1. Oviatt, A. A.; Jissy, A. K. et al, N. Biorg. Med. Chem. Lett. 2018.
2. Jissy, A. K. et al. J. Chem. Inf. Model 2019 Just Accepted.
3. Arencibia, J. M.; Brindani, N.; Jissy A. K. et al. J. Med. Chem., 2019, Submitted.
Scientific Talks
2019
Aug: Recipient of Promise in COMP Award: ACS Fall Meeting, San Diego, CA.
July: GRS CADD, Mount Snow, USA.
June: MSCA IF event on Antimicrobial Resistance, Barcelona, Spain.
May: 12th European Workshop in Drug Design, Siena, Italy.
Mar: 6th CDDD Meeting, Rome, Italy.
Poster Presentations
2019
July: GRC on Computer Aided Drug Design, USA.
March: 6th CDDD Meeting, Rome, Italy.
2018
September: 22nd EuroQSAR, Thessaloniki, Greece.
July: GRC, Computational Chemistry, VT, USA.; GRS & GRC, Topoisomerases, Mt. Holyoke, MA, USA.; CECAM Workshop on modeling metal ions, 2018, Paris, France.
June: BioExcel Summer School, Sardinia, Italy.
