Predicting Plasmodium falciparum kinase inhibitors from antimalarial medicinal herbs using computational modeling approach.

Malaria remains a significant public health challenge, with resistance to available drugs necessitating the development of novel therapies targeting invasion-dependent proteins. Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK-1) is essential for host erythrocyte invasion and parasite asexual development. This study screened a library of 490 compounds using computational methods to identify potential PfCDPK-1 inhibitors. Three compounds; 17-hydroxyazadiradione, Picracin, and Epicatechin-gallate derived from known antimalarial botanicals, showed potent inhibitory effects on PfCDPK-1. These compounds exhibited better binding affinities (-8.8, -9.1, -9.3 kCal/mol respectively), pharmacokinetics, and physicochemical properties than the purported inhibitory standard of PfCDPK-1, Purfalcamine. Molecular dynamics simulations (50 ns) and molecular mechanics analyses confirmed the stability and binding rigidity of these compounds at the active pocket of PfCDPK-1. The results suggest that these compounds are promising pharmacological targets with potential therapeutic effects for malaria treatment/management without undesirable side effects. Therefore, this study provides new insights into the development of effective antimalarial agents targeting invasion-dependent proteins, which could help combat the global malaria burden. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00175-z.

Africa (COVID-19) Vaccine Technology Transfer: Where Are We?

The rampant spread of the COVID-19 infection poses a grave and formidable challenge to global healthcare, with particular concern to the inhabitants of the African continent. In response to these pressing concerns, different strategies have been employed to combat the emergence of this insidious disease, encompassing crucial measures such as physical distancing, the utilization of face masks, meticulous hand hygiene, and widespread vaccination campaigns. Nevertheless, the economic realities faced by numerous African nations, characterized by their classification as "low-income countries (LICs)", present a formidable barrier to accessing and distributing approved vaccines to their populations. Moreover, it is essential to discuss the hesitancy of the European Union (EU) in releasing intellectual property rights associated with the transfer of vaccine technology to Africa. While the EU has been a key player in global efforts to combat the pandemic, there has been reluctance in sharing valuable knowledge and resources with African countries. This hesitancy raises concerns about equitable vaccine access and the potential for a prolonged health crisis in Africa. This review underscores the urgent imperative and need of establishing localized vaccine development and production facilities within Africa, necessitating the active involvement of governments and collaborative partnerships to achieve this crucial objective. Furthermore, this review advocates for the exploration of viable avenues for the transfer of vaccine technology as a means to facilitate equitable vaccine access across the African continent and also the cruciality and the need for the EU to reconsider its stance and actively engage in transferring vaccine technology to Africa through sharing intellectual property. The EU can contribute to the establishment of localized vaccine production facilities on the continent, which will not only increase vaccine availability but also promote self-sufficiency and resilience in the face of future health emergencies.

Proteome based analysis of circulating SARS-CoV-2 variants: approach to a universal vaccine candidate.

The discovery of the first infectious variant in Wuhan, China, in December 2019, has posed concerns over global health due to the spread of COVID-19 and subsequent variants. While the majority of patients experience flu-like symptoms such as cold and fever, a small percentage, particularly those with compromised immune systems, progress from mild illness to fatality. COVID-19 is caused by a RNA virus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our approach involved utilizing immunoinformatic to identify vaccine candidates with multiple epitopes and ligand-binding regions in reported SARS-CoV-2 variants. Through analysis of the spike glycoprotein, we identified dominant epitopes for T-cells and B-cells, resulting in a vaccine construct containing two helper T-cell epitopes, six cytotoxic T-cell epitopes, and four linear B-cell epitopes. Prior to conjugation with adjuvants and linkers, all epitopes were evaluated for antigenicity, toxicity, and allergenicity. Additionally, we assessed the vaccine Toll-Like Receptors complex (2, 3, and 4). The vaccine construct demonstrated antigenicity, non-toxicity, and non-allergenicity, thereby enabling the host to generate antibodies with favorable physicochemical characteristics. Furthermore, the 3D structure of the B-cell construct exhibited a ProSA-web z-score plot with a value of -1.71, indicating the reliability of the designed structure. The Ramachandran plot analysis revealed that 99.6% of the amino acid residues in the vaccine subunit were located in the high favored observation region, further establishing its strong candidacy as a vaccination option.

Structure-based computational design of novel covalent binders for the treatment of sickle cell disease.

The quest in finding an everlasting panacea to the pernicious impact of sickle cell disease (SCD) in the society hit a turn of success since the recent discovery of a small molecule reversible covalent inhibitor, Voxelotor. A drug that primarily promotes the stability of oxygenated hemoglobin and inhibit the polymerization of HbS by enhancing hemoglobin's affinity for oxygen has opened a new frontier in drug discovery and development. Despite eminent efforts made to reproduce small molecules with better therapeutic targets, none has been successful. To this end, we employed the use of structure-based computational techniques with emphasis on the electrophilic warhead group of Voxelotor to harness novel covalent binders that could elicit better therapeutic response against HbS. The PubChem database and DataWarrior software were used to design random molecules using Voxelotor's electrophilic functionality. Following the compilation of these chemical entities, a high-throughput covalent docking-based virtual screening campaign was conducted which revealed three (Compound_166, Compound_2301, and Compound_2335) putative druglike candidates with higher baseline energy value compared to the standard drug. Subsequently, in silico ADMET profiling was carried out to evaluate their pharmacokinetics and pharmacodynamics properties, and their stability was evaluated for 1 µs (1 µs) using molecular dynamics simulation. Finally, to prioritize these compounds for further development in drug discovery, MM/PBSA calculations was employed to evaluate their molecular interactions and solvation energy within the HbS protein. Despite the admirable druglike and stability properties of these compounds, further experimental validations are required to establish their preclinical relevance for drug development.

Bioinformatics analysis of structural protein to approach a vaccine candidate against Vibrio cholerae infection.

The bacteria Vibrio cholerae causes cholera, an acute diarrheal infection that can lead to dehydration and even death. Over 100,000 people die each year as a result of epidemic diseases; vaccination has emerged as a successful strategy for combating cholera. This study uses bioinformatics tools to create a multi-epitope vaccine against cholera infection using five structural polyproteins from the V. cholerae (CTB, TCPA, TCPF, OMPU, and OMPW). The antigenic retrieved protein sequence were analyzed using BCPred and IEDB bioinformatics tools to predict B cell and T cell epitopes, respectively, which were then linked with flexible linkers together with an adjuvant to boost it immunogenicity. The construct has a theoretical PI of 6.09, a molecular weight of 53.85 kDa, and an estimated half-life for mammalian reticulocytes in vitro of 4.4 h. These results demonstrate the construct's longevity. The vaccine design was docked against the human toll-like receptor (TLR) to evaluate compatibility and effectiveness; also other additional post-vaccination assessments were carried out on the designed vaccine. Through in silico cloning, its expression was determined. The results show that it has a CAI value of 0.1 and GC contents of 58.97% which established the adequate expression and downstream processing of the vaccine construct, and our research demonstrated that the multi-epitope subunit vaccine exhibits antigenic characteristics. Additionally, we carried out an in silico immunological simulation to examine the immune reaction to an injection. Our results strongly suggest that the vaccine candidate on further validation would induce immune response against the V. cholerae infection.

Immunoinformatics design of multi-epitope peptide for the diagnosis of Schistosoma haematobium infection.

Schistosoma haematobium has been identified as a significant cause of urogenital disease, as well as a risk factor for bladder cancer and HIV/AIDS. The parasites are obtained trans-dermally by swimming or wading in contaminated freshwater, and they are also transmitted to humans by freshwater snails. The organisms infect the vasculature of the gastrointestinal or genitourinary tracts. Worms live in blood vessels and lay eggs that become embedded in the bladder wall, causing chronic immune-mediated disease and squamous cell carcinoma growth. The primary goal of this research is to predict and design a novel synthetic protein containing multiple immunodominant B cell epitopes using three schistosome proteins: XP-012801068.2, XP-012801892.2, and XP-012793835.2 softwares were used to analyze the proteins' primary, secondary, and tertiary structures (BepiPred, BcPred).The B cell construct was then evaluated using I-TASSER server, and physicochemical properties, as well as homology modeling of the 3 D structure of the protein, was obtained. In silico analyses revealed regions with high immunogenicity. For XP-012801068.2, three epitopes are found between residues 292-334, 3-22, and 314-333; for XP-012801892.2, three epitopes are found in the residues 184-236, 81-100, and 329-348 for XP-012793835.2, four epitopes are found in the residues 185-222, 469-512, 649-713, and 338-357. The construct's has an average length of 308 bp, instability index of 49.96, theoretical PI of 4.2 and a C score -1.59. Furthermore, these parameters analyzed reveals that the constructed multi-epitope peptide has the potential to provide a theoretical basis for the development of a Schistosoma haematobium diagnostic kit.Communicated by Ramaswamy H. Sarma.