Computer-aided drug design CADD

Virtual screening, molecular docking and lead optimisation against targets of therapeutic interest, validated by simulation.

5 projects

Application of integrated computational strategies for the identification and prioritization of human telomerase inhibitors as a therapeutic approach against cancer

Amanda Macedo LeandroMSc.

Human telomerase is reactivated in the majority of tumors and plays a central role in telomere maintenance and the unlimited proliferative capacity of cancer cells, making its catalytic subunit, hTERT, a promising target for the development of new therapeutic strategies. This project proposes the development and application of integrated computational strategies for the identification and prioritization of potential human telomerase inhibitors. The approach combines virtual screening, different docking and rescoring methods, protein-ligand interaction analysis, and molecular dynamics. Strategies will be explored to increase the robustness of candidate prioritization, as well as to expand the chemical diversity of the selected set. Thus, the project aims to establish a systematic and robust computational workflow capable of exploring large chemical libraries and selecting structurally diverse candidates with greater potential for interaction with telomerase.

Team: Amanda Macedo Leandro, Danielle Jesus Marques

Ligand prospecting via automated virtual screening: In silico validation of the TcPAQR4 receptor as a pharmacological target

Ana Clara Magalhães Gomes

The etiological agent of Chagas disease is the protozoan Trypanosoma cruzi, a parasite that infects mammals. In a previous study, it was discovered that the TcPAQR4 receptor plays an essential role in parasite infectivity. Consequently, virtual screening of small molecules targeting the receptor, rescoring, and interaction profiling of the most promising ligands were previously performed by master's student Maria Clara Esteves Monachesi. Therefore, the present project aimed to validate the previously developed methodology by further investigating receptor structure energy minimization and expanding the number of evaluated poses to three. The comparison of results seeks to identify a molecule shared across both analyses that shows the greatest promise as an inhibitor of the target protein.

Team: Maria Clara Esteves Monachesi, Pedro Henrique Monteiro Torres

Allosteric modulation of the Trypanosoma cruzi trypanothione reductase enzyme: A screening study guided by dynamic and structural characterization

Guilherme SpeltaMSc.

Chagas disease, caused by infection with Trypanosoma cruzi, is the most lethal parasitic disease in the Americas. Trypanosomatids possess a unique oxidative stress control pathway that is absent in humans, making it an attractive target for drug development due to its essential role in parasite survival. Within this pathway, trypanothione reductase is a key enzyme responsible for maintaining redox balance in the parasite. This project aims to investigate the presence and relationship of cavities in T. cruzi trypanothione reductase with its active site using computational approaches, including molecular dynamics, normal mode analysis, and evolutionary conservation. The goal is to identify potential allosteric effects that may be explored for pharmacological intervention.

Team: Pedro Geraldo Pacutti, Guilherme Spelta, Heitor Azanha (estagiário)

Prospecting and investigating the antichagasic potential of candidate inhibitors targeting a membrane receptor of Trypanosoma cruzi (TcPAQR4).

Maria Clara Esteves MonachesiBSc.

Trypanosoma cruzi, the causative agent of Chagas disease, represents a major public health concern in many countries, including Brazil. Our group recently identified TcPAQR4, a T. cruzi homolog of the human Progestin and AdipoQ Receptors (hPAQRs), as a putative receptor for platelet-activating factor (PAF) and lyso-phosphatidylcholine (LPC). These receptors belong to the PAQR family, characterized by seven transmembrane domains (7TM). Throughout its complex life cycle, T. cruzi undergoes several morphological transitions between epimastigotes, trypomastigotes, and amastigotes, both in its insect vectors and mammalian hosts. Our findings indicate that TcPAQR4 plays a key role in the differentiation of epimastigotes into trypomastigotes in vitro, as well as during macrophage infection by trypomastigotes. Assays with TcPAQR4 knockdown parasites showed impaired responsiveness to PAF and LPC, confirming the receptor’s involvement in signal-mediated differentiation. In a previous study, we modeled TcPAQR4 and screened over 500k compounds from Enamine libraries for potential inhibitors using molecular docking followed by ligand-receptor analysis, and the 20 most promising molecules were chosen for further studies in vitro and in silico. In the current study, we are conducting molecular dynamics (MD) simulations of TcPAQR embedded in a T. cruzi trypomastigote membrane in five configurations: (1) ligand-free, (2) bound to PAF, (3) bound to LPC, (4) bound to WEB 2086 (a known PAFR inhibitor), and (5) bound to the most promising in vitro candidates.

Team: Eu, Ana Clara Magalhães, Pedro Torres, Angela Hampshire

Structure modeling and screening of potential inhibitors for Trypanosoma cruzi protein kinase TcMK2

Marianna Zuin Maia dos SantosBSc.

When the gene encoding TcMK2 is knocked out in T. cruzi, it is observed that the organisms fail to complete metacyclogenesis-the process in the parasite's life cycle where it differentiates from epimastigote to metacyclic trypomastigote. This project aims to model the structure and select potential inhibitors for TcMK2 using in silico approaches. The inhibition of this protein can serve as a strategy to analyze its importance in other stages of the parasite's life cycle and treating Chagas’ disease.