An in silico investigation of phytochemicals as potential inhibitors against non-structural protein 1 from dengue virus 4

Dengue fever has emerged as a big threat to human health since the last decade owing to high morbidity with considerable mortalities. The proposed study aims at the in silico investigation of the inhibitory action against DENV4-NS1 of phytochemicals from two local medicinal plants of Pakistan. Non-Structural Protein 1 of Dengue Virus 4 (DENV4-NS1) is known to be involved in the replication and maturation of viron in the host cells. A total of 129 phytochemicals (50 from Tanacetum parthenium and 79 from Silybum marianum) were selected for this study. The tertiary structure of DENV4-NS1 was predicted based on homology modelling using Modeller 9.18 and the structural stability was evaluated using molecular dynamics simulations. Absorption, distribution, metabolism, excretion and toxicity (ADMET) along with the drug-likeness was also predicted for these phytochemicals using SwissADME and PreADMET servers. The results of ADMET and drug-likeness predictions exhibited that 54 phytochemicals i.e. 25 from Tanacetum parthenium and 29 from Silybum marianum showed effective druglikeness. These phytochemicals were docked against DENV4-NS1 using AutoDock Vina and 18 most suitable phytochemicals with binding affinities ≤ -6.0 kcal/mol were selected as potential inhibitors for DENV4-NS1. Proposed study also exploits the novel inhibitory action of Jaceidin, Centaureidin, Artecanin, Secotanaparthenolide, Artematin, Schizolaenone B, Isopomiferin, 6, 8-Diprenyleriodictyol, and Anthraxin against dengue virus. It is concluded that the screened 18 phytochemicals have strong inhibition potential against Dengue Virus 4.

Probing the Pharmacological Parameters, Molecular Docking and Quantum Computations of Plant Derived Compounds Exhibiting Strong Inhibitory Potential Against NS5 from Zika Virus

ABSTRACT Zika virus (ZIKV) is known for microcephaly and neurological disease in humans and the nonstructural proteins of ZIKV play a fundamental role in the viral replication. Among the seven nonstructural proteins, NS5 is the most conserved and largest protein. Two major functional domains of NS5 i.e. methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp) are imperative for the virus life cycle and survival. The present study explicates the inhibitory action of phytochemicals from medicinal plants against NS5 from ZIKV, leading to the identification of potential inhibitors. The crystal structure of the protein is retrieved from RCSB protein data bank. A total of 2035 phytochemicals from 505 various medicinal plants are analysed for their pharmacological properties and pharmacokinetics. Compounds having effective drug-likeness are docked against the protein and further analysed using density functional theory approach. Among the 2035 phytochemicals, 13 are selected as potential inhibitors against MTase having high binding affinities and 17 compounds are selected for RdRp. HOMO and LUMO energies are calculated for the docked compounds within and outside binding pockets of MTase and RdRp, adapting the B3LYP hybrid exchange-correlation functional with def2-SV(P) basis set. Physicochemical properties such as ionization energy, electronic chemical potential, electronegativity, electron affinity, molecular softness, molecular hardness and electrophilicity index have also been analysed for selected phytochemicals. Based upon the results, it is concluded that the selected phytochemicals are highly competent to impede the replication of the virus by inhibiting the ZIKV-NS5.