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Aim: To establish, through molecular modelling, safe and clinically acceptable putative antagonists of E571K-mutated exportin-1 among the bioactive compounds in various parts of Juglans mandshurica. Methods: The bioactive compounds were subjected to compendium of druglikeness and lead-likeness filter workflows prior to docking of the resultant compounds into E571K exportin-1 active site using PyRx AutoDock vina to establish their binding affinity and interaction profile. The evolutionary algorithm of Osiris property explorer DataWarrior software as well as lead-likeness filter were employed for generation of novel non-promiscuous analogues of the lead compound with better putative selectivity and clinical acceptability as E571K Exportin-1 antagonists.Results: The findings of this study present taxifolin as the putatively effective and lead-like E571K Exportin-1 inhibitor with high potential of qualifying for clinical evaluation but is associated with high promiscuity tendency in high throughput screening. The evolutionary derivation of novel analogues of the compound, however, results in the generation of putatively non-promiscuous, non-toxic, and lead-like E571K Exportin-1 antagonists with high synthetic accessibility and clinical developability for evaluation in the strategy for treatment of drug-resistant KRAS-mutant lung adenocarcinoma condition.

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Depression is one of the most common mood disorders among psychiatric diseases, affecting about 10% of the adult population. Animal models are used to aid the understanding of its pathogenesis and search for therapies. Some of the models of stress generate animals that are susceptible to stress while others are resilient. Thus, this study aimed to determine the similarities and/or differences in the genes responsible for susceptibility to chronic unpredictable stress (CUS)-induced depression-like behaviors in male and female Wistar rats. Sixty (30 male and 30 female) Wistar rats weighing between 120 & 150g were used for this study. The rats were randomly divided into two main groups: A (male) and B (female). Rats in each main group were further divided into control (10) and test groups (20). Rats in the test groups were subjected to CUS (Willner, 2017). Depression-like behaviors were assessed using a battery of behavioral tests. Rats in the CUS-susceptible group were sacrificed and the hippocampus excised. gDNAwasextracted from the hippocampal samples and purified. Purified DNA was subjected to whole genome sequencing (WGS). Base-calling of sequence reads from raw sequencing signal(FAST5) files was carried outand variants were called from alignment BAM files.Genes were identified, their impacts estimated, and variants annotated.60% of each of the male and female rats subjected to CUS showed significant (p<0.05) depression-like behaviors. WGS of the hippocampal DNA revealed atotal of 289,839 SNPsvariant types,7002insertions,34,459 deletions, and 1,570,186 single nucleotide polymorphisms(SNPs)variant types, 109,860insertions, 597,241 deletionsin CUS-susceptible male and female Wistar rats respectively.A total of 6 and 22 genes are implicated in increased susceptibility to depression in male and female Wistar rats respectively (M: F = 1:3.7).