Targeting cytochrome bc1 of Plasmodium falciparum

Abstract

Malaria is a life-threatening disease and a global health problem caused by Plasmodium parasite. Chemotherapy is essential to manage malarial infections, but the parasite is rapidly developing resistance against the available drugs. Thus, there is an urgent need to develop new drugs with increased potency. A promising target is that of atovaquone, inhibiting cytochrome bc1 (cyt bc1) complex of the mitochondrial electron transport chain. The study aimed to undertake in silico and in vitro studies to identify novel Plasmodium cyt bc1 complex inhibitors with specific affinity for Plasmodia and reduced toxicity profile. To fulfil this aim, a database of small organic compounds targeting Plasmodium cyt bc1 complex was created by collating data about chemical structures and their biological activities from published research. This facilitated the distinction between active and inactive inhibitors across various chemical scaffolds, aiding in the identification of lead compounds for further optimisation. This study evaluated a series of 1,4-naphthoquinone-1,2,3-triazole hybrids for their potential as antimalarial agents targeting resistant Plasmodium strain through in vitro investigations. Additionally, in silico studies were performed to examine the ligand binding interactions using molecular dynamic simulations in both wild-type and mutant models, along with predicting pharmacokinetic properties and drug-likeness. Furthermore, a series of 2-(4-substituted piperazin-1-yl)-N-(5-((naphthalen-2-yloxy)methyl)-1,3,4-thiadiazol-2-yl) acetamide hybrids previously reported as P. falciparum dihydrofolate reductase (DHFR) inhibitors were evaluated in vitro for their cytotoxicity against HEK293 and K562 cell lines, and in silico to determine their potential to target the cyt bc1 complex utilising molecular modelling methods involving, molecular docking, molecular dynamics simulations, and binding free energy (MM- GBSA) calculations to assess their binding affinity, stability, and key interactions. Moreover, novel chalcone compounds were designed engaging the principle of computer aided drug discovery and the ligands were virtually investigated for their antimalarial potential against atovaquone-resistant (Y279S) model using the Schrödinger software suite, followed by in silico evaluation of their drug-likeness and absorption, distribution, metabolism, elimination, toxicological (ADMET) properties. Overall, the thesis involved both the in vitro and in silico methods for evaluation of antimalarial potential and drug-likeness properties of compounds, highlighting the value of in silico approaches in early-stage drug discovery.