Informatics in Medicine Unlocked (Jan 2023)
In silico identification of potential PvFKBP35 inhibitors from Entadrophragma angolense Limonoids extracts as antimalarial agents
Abstract
Plasmodium species, which are spread by female Anopheles mosquitoes, are responsible for malaria. Out of the five major Plasmodium species, Plasmodium falciparum and Plasmodium vivax are the most deadly and invasive species responsible for 99.7% and 75% of malaria cases in Africa and America respectively. Despite the invasive nature of malaria, the Plasmodium parasite continues to develop resistance to current drugs. It is therefore imperative to come up with new therapeutics to combat malaria. Previous studies have reported that Limonoids from the Meliaceae family possess antimalarial properties. This study therefore aims at employing computational approaches to identify potential antimalarial Limonoids by targeting PvFKBP35. PvFKBP35 has been reported to be a suitable target for antimalarial therapeutics as it is involved in various physiological activities including transcription, protein stability and folding. Molecular docking, Molecular Dynamics simulation and Molecular Mechanics-Poisson Boltzmann Surface Area calculation were employed to identify the potential leads. Sixteen [16] Limonoids extracted from the bark of the stem of Entadrophragma angolense were virtually screened against PvFKPB35. The top hit compounds were subjected to 500 ns Molecular Dynamics simulation and Molecular Mechanics – Poisson Boltzmann Surface Area calculations to examine their stability and free binding energy. Two potential leads, compounds 1 and 11 with binding energies −6.3 and −5.4 kcal/mol respectively were identified. The potential leads in complexed with PvFKBP35 had an average root mean square deviation of 1.18 ± 0.19 Å and 3.12 ± 0.60 Å, indicating their stability. Solvent Accessible Surface Area was utilized to predict the penetrative ability of the compounds into the binding pocket. Average Solvent Accessible Surface Area values of 327.88 ± 47.54 A2, 402.18 ± 39.81 A2 were obtained for compounds 1 and 11 respectively. ADMET estimations of compounds 1 and 11 predicted them to be druglike and do not violate Lipinski's rule of five. Compounds 1 and 11 need be tested in vitro to validate their antimalarial activity although they were predicted to be antiprotozoal with Pa values 0.207 and 0.162. These compounds can then serve as the scaffold for the design of novel antimalarial therapeutics.
