Bridging the Gap in Malaria Parasite Resistance, Current Interventions, and the Way Forward from in Silico Perspective: A Review.

The past decade has seen most antimalarial drugs lose their clinical potency stemming from parasite resistance. Despite immense efforts by researchers to mitigate this global scourge, a breakthrough is yet to be achieved, as most current malaria chemotherapies suffer the same fate. Though the etiology of parasite resistance is not well understood, the parasite's complex life has been implicated. A drug-combination therapy with artemisinin as the central drug, artemisinin-based combination therapy (ACT), is currently the preferred malaria chemotherapy in most endemic zones. The emerging concern of parasite resistance to artemisinin, however, has compromised this treatment paradigm. Membrane-bound Ca2+-transporting ATPase and endocytosis pathway protein, Kelch13, among others, are identified as drivers in plasmodium parasite resistance to artemisinin. To mitigate parasite resistance to current chemotherapy, computer-aided drug design (CADD) techniques have been employed in the discovery of novel drug targets and the development of small molecule inhibitors to provide an intriguing alternative for malaria treatment. The evolution of plasmepsins, a class of aspartyl acid proteases, has gained tremendous attention in drug discovery, especially the non-food vacuole. They are expressed at multi-stage of the parasite's life cycle and involve in hepatocytes' egress, invasion, and dissemination of the parasite within the human host, further highlighting their essentiality. In silico exploration of non-food vacuole plasmepsin, PMIX and PMX unearthed the dual enzymatic inhibitory mechanism of the WM382 and 49c, novel plasmepsin inhibitors presently spearheading the search for potent antimalarial. These inhibitors impose structural compactness on the protease, distorting the characteristic twist motion. Pharmacophore modeling and structure activity of these compounds led to the generation of hits with better affinity and inhibitory prowess towards PMIX and PMX. Despite these headways, the major obstacle in targeting PM is the structural homogeneity among its members and to human Cathepsin D. The incorporation of CADD techniques described in the study at early stages of drug discovery could help in selective inhibition to augment malaria chemotherapy.

Assessment of urogenital schistosomiasis among basic school children in selected communities along major rivers in the central region of Ghana.

INTRODUCTION: urogenital schistosomiasis affects school-aged children with impacts on health, growth, and cognitive development. Basic schools along active water bodies have a possibility of a high infection among the children. METHODS: we performed a school-based cross-sectional assessment of urogenital schistosomiasis among children in four selected rural communities along major rivers in the central region of Ghana. Three hundred and nine (309) basic school children class 1 to junior high school (JHS) 3 were recruited. Sociodemographic data and information on behavioral influences were collected with a structured written questionnaire. Laboratory examinations were conducted on fresh urine samples. Descriptive statistics and cross-tabulations with measures of association between variables, adjusted and unadjusted logistic regression analysis were performed on measured variables. RESULTS: we recorded a 10.4% prevalence of urogenital schistosomiasis. Schools in communities along the Kakum river recorded the highest disease burden (65.6%). The odds of infection among pupils who engage in irrigation activities were 4 folds more than those who do not engage in irrigation activities (adjusted odds ratio (aOR) (95%CI): 4.3 (1.6-12.1), P-value=0.005). Pupils of caregivers who resort to self-medication using local herbal concoctions had 14-fold more odds of infection compared to those who visit the health facility (aOR (95%CI): 14.4 (1.4-143.1), P-value=0.006). CONCLUSION: poor health-seeking behaviors and lack of access to health facilities influenced the disease proportion among the children in these endemic communities.

'Polymorphism-aided' Selective Targeting and Inhibition of Caspase-6 by a Novel Allosteric Inhibitor Towards Efficient Alzheimer's Disease Treatment.

The predominance of Alzheimer's disease (AD) among the aged remains a global challenge. As such, the search for alternative and effective therapeutic options continuous unabated. Among the therapeutic targets explored over the years toward impeding the progression of AD is caspase-6 (Casp6), although selectively targeting Casp6 remains a challenge due to high homology with other members of the caspase family. Methyl 3-[(2,3-dihydro-1-benzofuran-2-yl formamido) methyl]-5-(furan-2-amido) benzoate (C13), a novel allosteric inhibitor, is reportedly shown to exhibit selective inhibition against mutant human Casp6 variants (E35K). However, structural and atomistic insights accounting for the reported inhibitory prowess of C13 remains unresolved. In this study, we seek to unravel the mechanistic selectivity of C13 coupled with the complementary effects of E35K single-nucleotide polymorphism (SNP) relative to Casp6 inhibition. Analyses of binding dynamics revealed that the variant Lysine-35 mediated consistent high-affinity interactions with C13 at the allosteric site, possibly forming the molecular basis of the selectivity of C13 as well as its high binding free energy as estimated. Analysis of residue interaction network around Glu35 and Lys35 revealed prominent residue network distortions in the mutant Casp6 conformation evidenced by a decrease in node degree, reduced number of edges and an increase short in path length relative to a more compact conformation in the wild system. The relatively higher binding free energy of C13 coupled with the stronger intermolecular interactions elicited in the mutant conformation further suggests that the mutation E35K probably favours the inhibitory activity of C13. Further analysis of atomistic changes showed increased C-α atom deviations consistent with structural disorientations in the mutant Casp6. Structural Insights provided could open up a novel paradigm of structure-based design of selective allosteric inhibition of Casp6 towards the treatment of neurodegenerative diseases.

Exploring the ring potential of 2,4-diaminopyrimidine derivatives towards the identification of novel caspase-1 inhibitors in Alzheimer's disease therapy.

Pro-inflammatory activation of caspase-1 in the neurodegenerative pathway has been associated with age-dependent cognitive impairment and Alzheimer's disease (AD) in humans. A recent report highlighted 2,4-diaminopyrimidine ring as an essential fragment in the inhibition of human caspase-1. However, the role of the ring and its enzyme inhibitory mechanism is not thoroughly investigated at the molecular level. The purpose of this study is therefore in twofold: (1) to understand the enzyme binding mechanism of the 2,4-diaminopyrimidine ring and (2) to search for more potent caspase-1 inhibitors that contain the ring, using integrative per-residue energy decomposition (PRED) pharmacophore modeling. Ligand interaction profile of a reference compound revealed a peculiar hydrogen formation of the amino group of 2,4-diaminopyrimidine with active site residue Arg341, possibly forming the bases for its inhibitory prowess against caspase-1. A generated pharmacophore model for structure-based virtual screening identified compounds, ZINC724667, ZINC09908119, and ZINC09933770, as potential caspase-1 inhibitors that possessed desirable pharmacokinetic and physiochemical properties. Further analyses revealed active site residues, Arg179, Ser236, Cys285, Gln283, Ser339, and Arg341, as crucial to inhibitor binding by stabilizing and forming hydrogen bonds, hydrophobic, and pi-pi interactions with the 2,4-diaminopyrimidine rings. Common interaction patterns of the hits could have accounted for their selective and high-affinity ligand binding, which was characterized by notable disruptions in caspase-1 structural architecture. These compounds could further be explored as potential leads in the development of novel caspase-1 inhibitors.