In Vitro and In Silico Approaches for the Antileishmanial Activity Evaluations of Actinomycins Isolated from Novel Streptomyces smyrnaeus Strain UKAQ_23

Abstract

Leishmaniasis, a Neglected Tropical Parasitic Disease (NTPD), is induced by several Leishmania species and is disseminated through sandfly (Lutzomyia longipalpis) bites. The parasite has developed resistance to currently prescribed antileishmanial drugs, and it has become pertinent to the search for new antileishmanial agents. The current study aimed to investigate the in vitro and in silico antileishmanial activity of two newly sourced actinomycins, X2 and D, produced by the novel Streptomyces smyrnaeus strain UKAQ_23. The antileishmanial activity conducted on promastigotes and amastigotes of Leishmania major showed actinomycin X2 having half-maximal effective concentrations (EC50), at 2.10 ± 0.10 μg/mL and 0.10 ± 0.0 μg/mL, and selectivity index (SI) values of 0.048 and 1, respectively, while the actinomycin D exhibited EC50 at 1.90 ± 0.10 μg/mL and 0.10 ± 0.0 μg/mL, and SI values of 0.052 and 1. The molecular docking studies demonstrated squalene synthase as the most favorable antileishmanial target protein for both the actinomycins X2 and D, while the xanthine phosphoribosyltransferase was the least favorable target protein. The molecular dynamics simulations confirmed that both the actinomycins remained stable in the binding pocket during the simulations. Furthermore, the MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) binding energy calculations established that the actinomycin X2 is a better binder than the actinomycin D. In conclusion, both actinomycins X2 and D from Streptomyces smyrnaeus strain UKAQ_23 are promising antileishmanial drug candidates and have strong potential to be used for treating the currently drug-resistant leishmaniasis.

Antiprotozoal Activity of Thymoquinone (2-Isopropyl-5-methyl-1,4-benzoquinone) for the Treatment of Leishmania major-Induced Leishmaniasis: In Silico and In Vitro Studies

“…Fourier transform infrared spectroscopy (FT-IR) revealed that the procured TQ had the same spectroscopic spectrum as the standard TQ ( Figures S1 and S2, see Supplementary Materials ) [ 5 ].…”

“…Leishmaniasis is a neglected tropical parasitic disease (NTPD) disseminated by female phlebotomine sandflies. It is caused by various species of obligate intracellular Leishmania protozoan parasites [ 1 , 2 , 3 , 4 , 5 ]. In humans, the parasite grows and reproduces as an internal amastigote inside macrophage phagolysosomes [ 3 ].…”

“…The in vitro antileishmanial activity of TQ was evaluated against the promastigote and amastigote infectious stages of L. major. The in silico molecular docking studies were performed between TQ and 16 previously reported antileishmanial target proteins [ 5 ] through the detailed analyses of the intermolecular interactions between the targets and TQ. The MD simulation was performed between TQ and the most preferred antileishmanial target protein along with MMPBSA binding energy evaluations.…”

In Vitro and In Silico Approaches for the Evaluation of Antimicrobial Activity, Time-Kill Kinetics, and Anti-Biofilm Potential of Thymoquinone (2-Methyl-5-propan-2-ylcyclohexa-2,5-diene-1,4-dione) against Selected Human Pathogens

“…All systems were minimized for 5000 steps using the Steepest Descent technique, and convergence was achieved under the force limit of 1000 (kJ/mol/nm) to exclude any steric clashes. Later, all four minimized systems were separately equilibrated at NVT (Canonical ensemble: where moles, N; volume, V; and temperature, T were conserved) and NPT (Isothermal-Isobaric ensemble: where moles, N; pressure, P; and temperature, T were conserved) ensembles for 100 ps (50,000 steps) and 1000 ps (1,000,000 steps), respectively, using time steps 0.2 and 0.1 fs, at 300 K to ensure a fully converged systems for the production run [ 56 ].…”

“…For each of the three complexes, the production was run for 200 ns. The trajectory and energy data were recorded every 10 ps [ 56 ]. GROMACS simulation package (GROMACS 2020.4) [ 57 , 58 ] was used to perform MD simulations using CHARMM36m forcefield [ 59 ].…”