Biology subjects

Uzochukwu, I. C.

Publications and source records attributed to Uzochukwu, I. C..

3 recordsLinked to original sources

bioRxiv2020

The Structure-Based Virtual Screening for Natural Compounds that Bind with the Activating Receptors of Natural Killer Cells

AimThis study is aimed at prospecting for natural compounds that have strong binding affinity for the Activating Receptors of Natural Killer (NK) cells. BackgroundNK cells are responsible for the immunosurveillance of tumor and virally- infected cells. The cytotoxic potentials of this unique population of immune cells are triggered by the activating receptors. Through ligand-binding, these receptors induce the tyrosine phosphorylation of adapter proteins through their Immunoreceptor Tyrosine-based Activation Motif ITAM sequences and this triggers direct cytotoxicity and the production of cytokines through different signal pathways. ObjectiveTo computationally predict the selectivity, specificity, and efficacy of natural compounds to be used as immunostimulatory agents for cancer treatment. MethodIn this study, 1,697 natural compounds were obtained from 82 edible tropical plants through data mining. The molecular docking simulations of these compounds were executed against 18 activating NK cells receptor targets using the Python Prescription 0.8. An arbitrary docking score [≥] -7.0 kcal/mol was chosen as cut off value. Further screening for oral bioavailability, promiscuity, molecular complexity and pharmacokinetic properties using the Swissadme and pkCSM webservers. The ligand similarity analysis and phylogenetic analysis of the receptors was carried out with the ChemMine and Clustal Omega webservers respectively. Binding site analyses and bioactivity prediction were also done with the Protein-Ligand Interaction Profiler and Molinspiration webservers respectively. Normal mode analyses were carried out with the CABS-flex 2.0 server. ResultSeventeen bioactive and non-promiscuous lead compounds with good physicochemical and pharmacokinetic properties were identified. ConclusionFurther tests are required to evaluate the efficacy of the lead compounds.

bioinformatics↗

bioRxiv2020

IN SILICO SCREENING AND MOLECULAR DYNAMIC SIMULATION STUDIES OF POTENTIAL SMALL MOLECULE IMMUNOMODULATORS OF THE KIR2DS2 RECEPTOR

The World Health Organization reports that cancer is one of the most common causes of death worldwide and it accounted for an estimated 9.6 million deaths in 2018. As compared with chemotherapy or radiotherapy, immunotherapy offers a safer, less stressful and selective strategy in the destruction of cancer cells. The killer cell immunoglobulin-like receptor 2DS2 (KIR2DS2) expressed on Natural Killer (NK) cells are involved in signal transduction processes that produce pro-inflammatory cytokines and directly destroy cancer and virally infected cells. The aim of this study is to identify small molecules from natural products that have strong binding affinity with KIR2DS2 and possible bioactivity. A library of small molecule natural compounds obtained from edible African plants was used for in Silico molecular docking simulations of KIR2DS2 (PDBID: 1m4k) using Pyrx. An arbitrary docking score [≥] -7.0 kcal/mol was chosen as cut off value. Screening for drug-likeness and ligand efficiency was based on the molecular descriptors of the compounds as provided by Pubchem. Further screening for saturation, molar refractivity, promiscuity, pharmacokinetic properties, and bioactivity was done using SWISSADME, PKCSM, and Molinspiration respectively. The molecular dynamic simulation and analyses was done using the Galaxy webserver which uses the GROMACS software. Analyses of molecular dynamic simulation were done using Galaxy and MDWEB webservers. Gibberellin A20 and A29 were obtained as the lead compounds and they show better promise as drug candidates for KIR2DS2 than the standard. It is recommended that the immuno-stimulatory effect of the lead compounds on KIR2DS2 be further investigated.

bioinformatics↗

bioRxiv2019

In silico and in vitro Investigations of Antihelmintic Activities of some Selected Approved Drugs

The search for alternative methods to mitigate the drawbacks associated with wet laboratory drug discovery has been a major challenge in drug design and has limited the options available in the fight against most Neglected Tropical Diseases (NTDs) such as helminthiasis. We investigated the binding affinities of some approved drugs to Ascaris suum mitochondrial rhodoquinol fumarate reductase enzyme (MRFR),an essential enzyme for ascaris survival, and the possibility of repurposing these drugs as antihelmintic agents using in silico molecular docking and in vitro paralysis and mortality times of fifteen selected front runners.Two hundred approved drugs were selected from ZINC(R) database based on bioactivity scores while MRFR(PDB code, 3vra) was obtained from the Protein Data Bank (PDB). Both were prepared using AutoDock tools v.1.5.6 and Chimerav.1.9.The docking protocol was validated by computationally reproducing the binding of atpenin to MRFR. The selected approved drugs and the receptor were docked using AutoDockVina v. 4.0. The docking results were analyzed using PyMoL v. 1.4.1.The paralysis and mortality times of the identified frontrunners against Pheretima posthuma were determined in vitro and synergistic testings were done by the checkerboard method. Fifteen drugs had binding free energies between -7.825 to 11.025 kcal/mol while four of these drugs (mefloquine, doxycycline, mepacrine and proguanil) emerged as major frontrunners by both in silico and in vitro assessments. The paralysis and mortality times of the four drugs were between 0.33-0.50 hr as against 1.80-2.36 hr for albendazole. They were therefore predicted to have ability to affect MRFR in the same manner as atpenin hence, suggestive of potential antihelmintic activity. In vivo investigation of these frontrunner drugs is strongly recommended. Author SummaryFor decades, intestinal worm infections have been a major public health problem particularly in the tropical regions of the world with infection figures put at 5.3b [16]. This disease is often associated with poor hygiene and sanitation hence is predominant in the resource-poor nations with physical infrastructural deficit [8]. Children between the ages of 2-10 years are the most vulnerable by reason of their hand habits with morbidity leading to compromise of physical and cognitive development while several sufferers have had to live disability-adjusted life years as a consequence [12]. Efforts at implementing improved hygiene and mass deworming campaigns have not delivered the intended outcomes with many reports coming from clinicians regarding gradual development of resistance to the standard treatments [9]. Given the huge cost and time invested in traditional drug discovery and the rarity of this disease in regions of the world with the resources for research, no new drugs have been developed in the past two decades [18]. The advent of computational techniques in drug discovery has come to mitigate these drawbacks. This study exploited this technique to full effect and through laboratory assays and clinical investigation of selected approved drugs, mepacrine and doxycycline were identified as potential antihelmintic agents fit for combination therapy.

cell biology↗