COMPUTATIONAL SIMULATIONS AS TOOLS IN THE SEARCH FOR THERAPIES AGAINST INFECTIOUS DISEASES AND CANCER

The computational advancements of the last decades have enabled the study of complex biological systems through computational simulations, with emphasis on Molecular Dynamics (MD). The need for new therapies for infectious diseases and cancer drives the search for new targets and mechanisms of action. Antimicrobial peptides (AMPs), such as the Polybia-MP1 (MP1) from the Brazilian wasp Polybia paulista, have shown potential against bacteria and cancer cells. Simultaneously, flaviviruses such as Dengue, Zika, and West Nile represent serious threats to public health, using the envelope protein (E) to invade host cells. This protein undergoes pH- and temperature-dependent conformational changes essential for fusion with the cell membrane and release of viral RNA. The Group of Computer Simulations of Liquid Systems (SSiLiq) from the Department of Physics at IBILCE/UNESP has been using computational simulations, particularly MD, to investigate the underlying molecular characteristics that govern the antibiotic and anticancer action of MP1 and some of its known synthetic analogs, and the stability of the flavivirus E protein dimer, especially Dengue, as a function of pH and temperature. In partnership with national and international theoretical and experimental groups, and using equilibrium MD simulations, enhanced sampling methods, and CpHMD (Constant pH Molecular Dynamics) with atomistic modeling, our group has reproduced in silico the adsorption process on bacterial and cancer cell membrane models and the subsequent folding of MP1 and some of its synthetic analogs. Regarding studies about the Dengue virus E protein, we have been able to map the most relevant residues to the stability of the dimer, which is the basic unit that makes up the viral envelope at neutral pH. We have also described the interaction surface between domain II of the E protein and a late endosome cell membrane model. Based on these results, we present the perspectives of future studies and collaborations with the potential to contribute to the development of antibiotic, chemotherapeutic, and antiviral compounds.

This work was supported by CNPq (409272/2021-3) and FAPESP (2022/00347-0, 2023/09944-3 and 2022/07231-7)