Anti-parasitic drug discovery against Babesia microti by natural compounds: an extensive computational drug design approach

Abstract

Tick-borne Babesiosis is a parasitic infection caused by Babesia microti that can infect both animals and humans and may spread by tick, blood transfusions, and organ transplantation. The current therapeutic options for B. microti are limited, and drug resistance is a concern. This study proposes using computational drug design approaches to find and design an effective drug against B. microti. The study investigated the potentiality of nine natural compounds against the pathogenic human B. microti parasite and identified Vasicinone and Evodiamine as the most promising drugs. The ligand structures were optimized using density functional theory, molecular docking, molecular dynamics simulations, quantum mechanics such as HOMO-LUMO, drug-likeness and theoretical absorption, distribution, metabolism, excretion, and toxicity (ADMET), and pharmacokinetics characteristics performed. The results showed that Vasicinone (-8.6 kcal/mol and -7.8 kcal/mol) and Evodiamine (-8.7 kcal/mol and -8.5 kcal/mol) had the highest binding energy and anti-parasitic activity against B. microti lactate dehydrogenase and B. microti lactate dehydrogenase apo form. The strongest binding energy was reported by Vasicinone and Evodiamine; the compounds were evaluated through molecular dynamics simulation at 100 ns, and their stability when they form complexes with the targeted receptors was determined. Finally, the pkCSM web server is employed to predict the ADMET qualities of specific molecules, which can help prevent negative effects that arise from taking the treatment. The SwissADME web server is used to assess the Lipinski rule of five and drug-likeness properties including topological polar surface area and bioavailability. The Lipinski rule is used to estimate significant drug-likeness. The theoretical pharmacokinetics analysis and drug-likeness of the selected compounds are confirmed to be accepted by the Lipinski rule and have better ADMET features. Thus, to confirm their experimental value, these mentioned molecules should be suggested to carry out in wet lab, pre-clinical, and clinical levels.

Keywords: ADMET; B. microti; DFT; and drug design; molecular docking; molecular dynamic simulation.

Figure 1

Molecular structures of selected compounds.

Figure 2

Three-dimensional protein structure of the Babesia microti.

Figure 3

Docking interactions between the proposed compound.

Figure 4

The molecular dynamics simulation of C1, C2, C3, and C4 complexes, where (A–D) designate RMSD, Rg, SASA, and hydrogen bond respectively.

Figure 5

The MMPBSA binding free energy of the Evodiamine complex, Vasicinone complex, and Standard Diminazene complexes. The overall MD simulation study suggests that these two hit complexes could be used as a lead compound.

Figure 6

Ca-residue cross-correlation profiles for the Evodiamine complex (A), Vasicinone complex (B), docked protein (C), and the standard Diminazene (D).

Figure 7

Diagram of the Frontier molecular orbital.