Closing the Gap: An Atomistic Structural and Functional Perspective of S. mansoni Universal Stress G4LZI3 Protein in Complex with Phenolic Compounds.

BACKGROUND: For decades, Praziquantel has been the undisputed drug of choice for all schistosome infections, but rising concerns due to the unelucidated mechanism of action of the drug and unavoidable reports of emerging drug resistant strains has necessitated the need for alternative treatment drug. Moreover, current apprehension has been reinforced by total dependence on the drug for treatment hence, the search for novel and effective anti-schistosomal drugs. METHODS: This study made use of bioinformatic tools to determine the structural binding of the Universal G4LZI3 Stress Protein (USP) in complex with ten polyphenol compounds, thereby highlighting the effectiveness of these recently identified 'lead' molecules in the design of novel therapeutics targeted against schistosomiasis. Upregulation of the G4LZI3 USP throughout the schistosome multifaceted developmental cycle sparks interest in its potential role as a druggable target. The integration of in silico tools provides an atomistic perspective into the binding of potential inhibitors to target proteins. This study therefore, implemented the use of Molecular Dynamic (MD) simulations to provide functional and structural insight into key conformational changes upon binding of G4- ZLI3 to these key phenolic compounds. RESULTS: Post-MD analyses revealed unique structural and conformational changes in the G4LZI3 protein in complex with curcumin and catechin respectively. These systems exhibited the highest binding energies, while the major interacting residues conserved in all the complexes provides a route map for structure-based drug design of novel compounds with enhanced inhibitory potency against the G4LZI3 protein. CONCLUSION: This study suggests an alternative approach for the development of anti-schistosomal drugs using natural compounds.

Integrating Bioinformatics Strategies in Cancer Immunotherapy: Current and Future Perspectives.

For the past few decades, the mechanisms of immune responses to cancer have been exploited extensively and significant attention has been given into utilizing the therapeutic potential of the immune system. Cancer immunotherapy has been established as a promising innovative treatment for many forms of cancer. Immunotherapy has gained its prominence through various strategies, including cancer vaccines, monoclonal antibodies (mAbs), adoptive T cell cancer therapy, and immune checkpoint therapy. However, the full potential of cancer immunotherapy is yet to be attained. Recent studies have identified the use of bioinformatics tools as a viable option to help transform the treatment paradigm of several tumors by providing a therapeutically efficient method of cataloging, predicting and selecting immunotherapeutic targets, which are known bottlenecks in the application of immunotherapy. Herein, we gave an insightful overview of the types of immunotherapy techniques used currently, their mechanisms of action, and discussed some bioinformatics tools and databases applied in the immunotherapy of cancer. This review also provides some future perspectives in the use of bioinformatics tools for immunotherapy.

Human Rhinovirus Inhibition Through Capsid "Canyon" Perturbation: Structural Insights into The Role of a Novel Benzothiophene Derivative.

The challenge in targeting human rhinoviruses (HRV) over the years has been attributed to the wide variety in HRV serotypes. Nonetheless, the search for therapeutic agents against HRV continues unabated. These efforts have been augmented by the recent discovery of the novel benzothiophene derivative shown to inhibit HRV viral replication. Bound to subtype HRV-B14, the compound showed similar inhibitory activity as Pleconaril, a known capsid inhibitor. However, the molecular and structural basis of this inhibition remains unclear. In this in silico report, residue interaction network analysis revealed that the binding of the benzothiophene derivative into the "canyon" region of the active site of HRV-B14 distorts its initially extensively networked and compact residue profile. This was characterized by fewer inter-residue hydrogen bonds, reduced van der Waals interactions, and increased residue flexibility. Interestingly, however, the binding of this benzothiophene derivative decreased the flexibility of the north-south wall around the canyon region possibly impeding the "breathing motion" of HRV-B14, hence its inhibition. Atomistic insights also revealed the cruciality of Tyr152 toward inhibitor binding at HRV-B14. This was justified by the amino acid's high intermolecular interaction with both inhibitors. Findings provide important structural insights in the inhibitory activity the novel benzothiophene derivative, and reaffirm its promising potential as an alternative capsid inhibitor toward common cold therapy upon further experimental validation.

Tweaking α -Galactoceramides: Probing the Dynamical Mechanisms of Improved Recognition for Invariant Natural Killer T-cell Receptor in Cancer Immunotherapeutics.

BACKGROUND: The last few decades have witnessed groundbreaking research geared towards immune surveillance mechanisms and have yielded significant improvements in the field of cancer immunotherapy. This approach narrows down on the development of therapeutic agents that either activate or enhance the recognitive function of the immune system to facilitate the destruction of malignant cells. The α -galactosylceramide derivative, KRN7000, is an immunotherapeutic agent that has gained attention due to its pharmacological ability to activate CD1d-restricted invariant natural killer T(iNKT) cells with notable potency against cancer cells in mouse models; a therapeutic success was not well replicated in human models. Dual structural modification of KRN7000 entailing the incorporation of hydrocinnamoyl ester on C6" and C4-OH truncation of the sphingoid base led to the development of AH10-7 which, interestingly, exhibited high potency in human cells. OBJECTIVE/METHODS: Therefore, to gain molecular insights into the structural dynamics and selective mechanisms of AH10-7 for human variants, we employed integrative molecular dynamics simulations and thermodynamic calculations to investigate the inhibitory activities of KRN7000 andAH10-7 on hTCR-CD1d towards activating iNKT. RESULTS: Interestingly, our findings revealed that AH10-7 exhibited higher affinity binding and structural effects on hTCR-CD1d, as mediated by the incorporated hydrocinnamoyl ester moiety which accounted for stronger intermolecular interactions with 'non-common' binding site residues. CONCLUSION: Findings extracted from this study further reveal important molecular and structural perspectives that could aid in the design of novel α-GalCer derivatives for cancer immunotherapeutics.

CF3 -Pyridinyl Substitution on Antimalarial Therapeutics: Probing Differential Ligand Binding and Dynamical Inhibitory Effects of a Novel Triazolopyrimidine-Based Inhibitor on Plasmodium falciparum Dihydroorotate Dehydrogenase.

The quest for reliable dihydroorotate dehydrogenase (DHODH) inhibitors has engendered the discovery of potential therapeutic compounds at different stages of clinical trials. Although promising, high attrition rates and unfavorable bioactivities have limited their drug developmental progress. A recent structural modification of DSM265, a triazolopyrimidine-based inhibitor, yielded DSM421, derived by the substitution of the SF5 -aniline group on DSM265 with a CF3 -pyridinyl moiety. Consequently, DSM421 exhibited improved pharmacological and pharmacokinetics attributes relative to DSM265. The improved bioactivity mediated by the CF3 -pyridinyl group leaves us with a curiosity to investigate underlying ligand-binding mechanisms and dynamics using computational methods. Presented in this study are insights that clearly explain the effects of structural SF5 -aniline→CF3 -pyridinyl modifications on pfDHODH inhibition. Findings showed that the CF3 -pyridinyl group induced an optimal and stabilized positioning of DSM421 within the binding pocket, allowing for steady and strong intermolecular interactions which favored its stronger binding affinity as estimated and correlated with bioactivity data. These interactions consequently induced a pronounced stabilization of the structural conformation of pfDHODH by restricting residue motions, which possibly underpinned its enhanced inhibitory activity relative to DSM265. Active site interactions of the CF3 -pyrinidyl group with residues Ser236, Ile237, and Phe188 characterized by strong π-π stacking and halogen interactions also stabilized its positioning which altogether accounted for its enhanced inhibitory prowess towards pfDHODH. On the contrary, fewer and weaker interactions characterized DSM265 binding which could explain its relatively lower binding affinity. Findings will facilitate the design of novel pfDHODH inhibitors with enhanced properties.

Unveiling a New Era in Malaria Therapeutics: A Tailored Molecular Approach Towards the Design of Plasmepsin IX Inhibitors.

The invasive tactics employed by the malarial parasite renders malaria a global health threat, further impeding the effective treatment of the mosquito borne-parasitic disease. Although there have been countless efforts directed towards the development of effective therapeutics, factors such as emerging strains of drug resistance, enhanced toxicity and poor pharmacokinetic properties of current therapeutics has hampered the drug discovery process resulting in the spread of this parasitic disease. A promising target of the most lethal strain of the Plasmodium species that plays a predicted role in erythrocyte invasion of the virulent malarial parasite is aspartic protease IX commonly referred to Plasmepsin IX. The integration of computer aided-drug design platforms has revolutionized the 21st century and has opened avenues to render a final "knock out" in the elimination and eradication of this parasitic disease Hitherto, this is the first attempt directed towards the design of therapeutics tailored explicitly to Plasmepsin IX. A potent peptidomimetic inhibitor referred to as 49c which is a known inhibitor of Plasmepsin II, has recently exhibited potent inhibitory activity against Plasmepsin IX. In-silico structural and physicochemical inspection of 49c displayed poor pharmacokinetic properties thus paving the way for the development of tailored inhibitors with desirable therapeutic properties against Plasmepsin IX. In this study we implement the pharmacophore model approach in combination with per-residue energy decomposition analysis to serve as a powerful cornerstone, that may assist medicinal experts in the composition of multifunctional therapeutics that may predispose factors such as cross-resistance and toxicity, with enhanced pharmacokinetic properties.

A dual target of Plasmepsin IX and X: Unveiling the atomistic superiority of a core chemical scaffold in malaria therapy.

Plasmepsin IX and X, members of the prominent aspartic family of proteases whose function were hitherto unknown have only recently been established as key mediators of erythrocyte invasion and egress of the virulent malarial parasite. Inhibitor 49c, a potent antimalarial peptidomimetic inhibitor initially developed to target Plasmepsin II has lately been proven to exhibit potent inhibitory activity against Plasmepsin IX and X. However, the molecular and structural dynamics supporting its inhibitory activity remain inconclusive. Hindering the motion of the flap and hinge region of an aspartic protease remains essential for disabling the catalytic activity of the enzyme. Integrating molecular dynamic simulations coupled with other advanced biocomputational tools, we reveal the enhanced structural mechanistic competence of 49c in complex with Plasmepsin IX and X relative to Pepstatin. Pepstatin, a known aspartic protease inhibitor which actively hinders the opening and closing of the flap tip and flexible loop and consequently limits access to the catalytic aspartic residues, however, its administration has been related to elevated levels of toxicity. Thermodynamic calculations reveal a higher relative binding free energy associated with Plasmepsin IX and X in complex with 49c as opposed to Pepstatin. A relatively compact and structurally rigid 49c bound complexes sequel into the restriction of the flap and hinge residues by restraining cohesive movement, consequently hindering their "twisting motion" from transpiring. Findings unveil an atomistic perspective into the structural superiority of 49c in complex with Plasmepsin IX and X.

Does Size Really Matter? Probing the Efficacy of Structural Reduction in the Optimization of Bioderived Compounds - A Computational "Proof-of-Concept".

Over the years, numerous synthetic approaches have been utilized in drug design to improve the pharmacological properties of naturally derived compounds and most importantly, minimize toxic effects associated with their transition to drugs. The reduction of complex bioderived compounds to simpler bioactive fragments has been identified as a viable strategy to develop lead compounds with improved activities and minimal toxicities. Although this 'reductive' strategy has been widely exemplified, underlying biological events remain unresolved, hence the unanswered question remains how does the fragmentation of a natural compound improve its bioactivity and reduce toxicities? Herein, using a combinatorial approach, we initialize a computational "proof-of- concept" to expound the differential pharmacological and antagonistic activities of a natural compound, Anguinomycin D, and its synthetic fragment, SB640 towards Exportin Chromosome Region Maintenance 1 (CRM1). Interestingly, our findings revealed that in comparison with the parent compound, SB640 exhibited improved pharmacological attributes, while toxicities and off-target activities were relatively minimal. Moreover, we observed that the reduced size of SB640 allowed 'deep access' at the Nuclear Export Signals (NES) binding groove of CRM1, which favored optimal and proximal positioning towards crucial residues while the presence of the long polyketide tail in Anguinomycin D constrained its burial at the hydrophobic groove. Furthermore, with regards to their antagonistic functions, structural inactivation (rigidity) was more pronounced in CRM1 when bound by SB640 as compared to Anguinomycin D. These findings provide essential insights that portray synthetic fragmentation of natural compounds as a feasible approach towards the discovery of potential leads in disease treatment.

Egress and invasion machinery of malaria: an in-depth look into the structural and functional features of the flap dynamics of plasmepsin IX and X.

Plasmepsins, a family of aspartic proteases expressed by Plasmodium falciparum parasite, have been identified as key mediators in the onset of lethal malaria. Precedence has been placed on this family of enzymes due their essential role in the virulence of the parasite, thus highlighting their importance as novel drug targets. A previously published study by our group proposed a set of parameters used to define the flap motion of aspartic proteases. These parameters were used in the study of Plm I-V and focused on the flap flexibility as well as structural dynamics. Recent studies have highlighted the essential role played by Plm IX and X in egress and invasion of the malarial parasite. This study aims to close the gap on the latter family, investigating the flap dynamics of Plms IX and X. Molecular dynamics simulations demonstrated an "open and close" mechanism at the region of the catalytic site. Further computation of the dihedral angles at the catalytic region revealed tractability at both the flap tip and flexible loop. This structural versatility enhances the interaction of variant ligand sizes, in comparison to other Plm family members. The results obtained from this study signify the essential role of structural flap dynamics and its resultant effect on the binding landscapes of Plm IX and X. We believe that this unique structural mechanism may be integrated in the design and development of effective anti-malarial drugs.