Cell-Penetrating Milk-Derived Peptides with a Non-Inflammatory Profile.

Milk-derived peptides are known to confer anti-inflammatory effects. We hypothesised that milk-derived cell-penetrating peptides might modulate inflammation in useful ways. Using computational techniques, we identified and synthesised peptides from the milk protein Alpha-S1-casein that were predicted to be cell-penetrating using a machine learning predictor. We modified the interpretation of the prediction results to consider the effects of histidine. Peptides were then selected for testing to determine their cell penetrability and anti-inflammatory effects using HeLa cells and J774.2 mouse macrophage cell lines. The selected peptides all showed cell penetrating behaviour, as judged using confocal microscopy of fluorescently labelled peptides. None of the peptides had an effect on either the NF-κB transcription factor or TNFα and IL-1ß secretion. Thus, the identified milk-derived sequences have the ability to be internalised into the cell without affecting cell homeostatic mechanisms such as NF-κB activation. These peptides are worthy of further investigation for other potential bioactivities or as a naturally derived carrier to promote the cellular internalisation of other active peptides.

Computational Screening of Neuropilin-1 Unveils Novel Potential Anti-SARS-CoV-2 Therapeutics.

Neuropilin 1 (NRP-1) inhibition has shown promise in reducing the infectivity of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and preventing the virus entry into nerve tissues, thereby mitigating neurological symptoms in COVID-19 patients. In this study, we employed virtual screening, including molecular docking, Molecular Dynamics (MD) simulation, and Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) calculations, to identify potential NRP-1 inhibitors. From a compendium of 1930 drug-like natural compounds, we identified five potential leads: CNP0435132, CNP0435311, CNP0424372, CNP0429647, and CNP0427474, displaying robust binding energies of -8.2, -8.1, -10.7, -8.2, and -8.2 kcal/mol, respectively. These compounds demonstrated interactions with critical residues Tyr297, Trp301, Thr316, Asp320, Ser346, Thr349, and Tyr353 located within the b1 subdomain of NRP-1. Furthermore, MD simulations and MM-PBSA calculations affirmed the stability of the complexes formed, with average root mean square deviation, radius of gyration, and solvent accessible surface area values of 0.118 nm, 1.516 nm, and 88.667 nm2 , respectively. Notably, these lead compounds were estimated to penetrate the blood-brain barrier and displayed antiviral properties, with Pa values ranging from 0.414 to 0.779. The antagonistic effects of these lead compounds merit further investigation, as they hold the potential to serve as foundational scaffolds for the development of innovative therapeutics aimed at reducing the neuroinfectivity of SARS-CoV-2.

Dual-Target Mycobacterium tuberculosis Inhibition: Insights into the Molecular Mechanism of Antifolate Drugs.

The escalating prevalence of drug-resistant strains of Mycobacterium tuberculosis has posed a significant challenge to global efforts in combating tuberculosis. To address this issue, innovative therapeutic strategies are required that target essential biochemical pathways while minimizing the potential for resistance development. The concept of dual targeting has gained prominence in drug discovery against resistance bacteria. Dual targeting recognizes the complexity of cellular processes and disrupts more than one vital pathway, simultaneously. By inhibiting more than one essential process required for bacterial growth and survival, the chances of developing resistance are substantially reduced. A previously reported study investigated the dual-targeting potential of a series of novel compounds against the folate pathway in Mycobacterium tuberculosis. Expanding on this study, we investigated the predictive pharmacokinetic profiling and the structural mechanism of inhibition of UCP1172, UCP1175, and UCP1063 on key enzymes, dihydrofolate reductase (DHFR) and 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione 5'-phosphate reductase (RV2671), involved in the folate pathway. Our findings indicate that the compounds demonstrate lipophilic physiochemical properties that promote gastrointestinal absorption, and may also inhibit the drug-metabolizing enzyme, cytochrome P450 3A4, thus enhancing their biological half-life. Furthermore, key catalytic residues (Serine, Threonine, and Aspartate), conserved in both enzymes, were found to participate in vital molecular interactions with UCP1172, which demonstrated the most favorable free binding energies to both DHFR and RV2671 (-41.63 kcal/mol, -48.04 kcal/mol, respectively). The presence of characteristic loop shifts, which are similar in both enzymes, also indicates a common inhibitory mechanism by UCP1172. This elucidation advances the understanding of UCP1172's dual inhibition mechanism against Mycobacterium tuberculosis.

Multi-dimensional structural footprint identification for the design of potential scaffolds targeting METTL3 in cancer treatment from natural compounds.

CONTEXT: [Formula: see text]-adenosine-methyltransferase (METTL3) is the catalytic domain of the 'writer' proteins which is involved in the post modifications of [Formula: see text]-methyladinosine ([Formula: see text]). Though its activities are essential in many biological processes, it has been implicated in several types of cancer. Thus, drug developers and researchers are relentlessly in search of small molecule inhibitors that can ameliorate the oncogenic activities of METTL3. Currently, STM2457 is a potent, highly selective inhibitor of METTL3 but is yet to be approved. METHODS: In this study, we employed structure-based virtual screening through consensus docking by using AutoDock Vina in PyRx interface and Glide virtual screening workflow of Schrodinger Glide. Thermodynamics via MM-PBSA calculations was further used to rank the compounds based on their total free binding energies. All atom molecular dynamics simulations were performed using AMBER 18 package. FF14SB force fields and Antechamber were used to parameterize the protein and compounds respectively. Post analysis of generated trajectories was analyzed with CPPTRAJ and PTRAJ modules incorporated in the AMBER package while Discovery studio and UCSF Chimera were used for visualization, and origin data tool used to plot all graphs. RESULTS: Three compounds with total free binding energies higher than STM2457 were selected for extended molecular dynamics simulations. The compounds, SANCDB0370, SANCDB0867, and SANCDB1033, exhibited stability and deeper penetration into the hydrophobic core of the protein. They engaged in relatively stronger intermolecular interactions involving hydrogen bonds with resultant increase in stability, reduced flexibility, and decrease in the surface area of the protein available for solvent interactions suggesting an induced folding of the catalytic domain. Furthermore, in silico pharmacokinetics and physicochemical analysis of the compounds revealed good properties suggesting these compounds could serve as promising MEETL3 entry inhibitors upon modifications and optimizations as presented by natural compounds. Further biochemical testing and experimentations would aid in the discovery of effective inhibitors against the berserk activities of METTL3.

Artificial Intelligence, Machine Learning, and Big Data for Ebola Virus Drug Discovery.

The effect of Ebola virus disease (EVD) is fatal and devastating, necessitating several efforts to identify potent biotherapeutic molecules. This review seeks to provide perspectives on complementing existing work on Ebola virus (EBOV) by discussing the role of machine learning (ML) techniques in the prediction of small molecule inhibitors of EBOV. Different ML algorithms have been used to predict anti-EBOV compounds, including Bayesian, support vector machine, and random forest algorithms, which present strong models with credible outcomes. The use of deep learning models for predicting anti-EBOV molecules is underutilized; therefore, we discuss how such models could be leveraged to develop fast, efficient, robust, and novel algorithms to aid in the discovery of anti-EBOV drugs. We further discuss the deep neural network as a plausible ML algorithm for predicting anti-EBOV compounds. We also summarize the plethora of data sources necessary for ML predictions in the form of systematic and comprehensive high-dimensional data. With ongoing efforts to eradicate EVD, the application of artificial intelligence-based ML to EBOV drug discovery research can promote data-driven decision making and may help to reduce the high attrition rates of compounds in the drug development pipeline.

Structural Insights into the Role of Pseudouridimycin Binding in Disruption of Bacterial RNA Polymerase Bridge Helix Conformational Arrangement.

BACKGROUND: The bridge helix (BH) is a crucial region in bacterial RNA polymerase (RNAP) catalysis. It plays an essential role in the nucleotide addition cycle (NAC) by performing many modulated rearrangements and conformational changes. Any changes in the bridge helix conformational arrangements could perturb the NAC. OBJECTIVE: Pseudouridimycin (PUM) was recently reported as a new RNAP inhibitor. However, the crucial role of the bridge helix in the inhibitory activity of PUM remains unclear, hence the aim of this study. METHODS: The PUM interaction and the structural dynamics of bacterial Bridge Helix upon PUM binding were investigated using various dynamic analysis approaches. RESULTS: Besides establishing the importance of the bridge helix residues in the binding of PUM, the findings of this study revealed that the adjacent binding of PUM induces a stabilized and structurally rigid bridge helix characterized by a reduction of individual residue flexibility, which could interfere with its role in the NAC. In addition, a hydrophobic structural rearrangement of the bridge helix is observed, evidenced by the burial and folding of residues into the hydrophobic core and a switch in the secondary structure of some regions of the bridge helix from the turn and bend to the alpha helix. The observed conformational disruption of the bridge helix upon binding of PUM also accounts for the reported inhibitory prowess and broad-spectrum activity as widely reported. Conclusion We believe findings from this study will further complement current drug discovery knowledge on disrupting bacterial RNAP machinery.

Characterization of the binding of MRTX1133 as an avenue for the discovery of potential KRASG12D inhibitors for cancer therapy.

The Kirsten rat sarcoma (KRAS) oncoprotein has been on drug hunters list for decades now. Initially considered undruggable, recent advances have successfully broken the jinx through covalent inhibition that exploits the mutated cys12 in the switch II binding pocket (KRASG12C). Though this approach has achieved some level of success, patients with mutations other than cys12 are still uncatered for. KRASG12D is the most frequent KRAS mutated oncoprotein. It is only until recently, MRTX1133 has been discovered as a potential inhibitor of KRASG12D. This study seeks to unravel the structural binding mechanism of MRTX1133 as well as identify potential drug leads of KRASG12D based on structural binding characteristics of MRTX1133. It was revealed that MRTX1133 binding stabilizes the binding site by increasing the hydrophobicity which resultantly induced positive correlated movements of switches I and II which could disrupt their interaction with effector and regulatory proteins. Furthermore, MRTX1133 interacted with critical residues; Asp69 (- 4.54 kcal/mol), His95 (- 3.65 kcal/mol), Met72 (- 2.27 kcal/mol), Thr58 (- 2.23 kcal/mol), Gln99 (- 2.03 kcal/mol), Arg68 (- 1.67 kcal/mol), Tyr96 (- 1.59 kcal/mol), Tyr64 (- 1.34 kcal/mol), Gly60 (- 1.25 kcal/mol), Asp12 (- 1.04 kcal/mol), and Val9 (- 1.03 kcal/mol) that contributed significantly to the total free binding energy of - 73.23 kcal/mol. Pharmacophore-based virtual screening based on the structural binding mechanisms of MRTX1133 identified ZINC78453217, ZINC70875226 and ZINC64890902 as potential KRASG12D inhibitors. Further, structural optimisations and biochemical testing of these compounds would assist in the discovery of effective KRASG12D inhibitors.

Molecular Modelling and Atomistic Insights into the Binding Mechanism of MmpL3 Mtb.

Mycobacterial membrane proteins Large (MmpLs), which belong to the resistance, nodulation, and division (RND) protein superfamily, play critical roles in transporting polymers, lipids, and immunomodulators. MmpLs have become one of the important therapeutic drug targets to emerge in recent times. In this study, two homology modelling techniques, Modeller and SWISS-MODEL, were used in modelling the three-dimensional protein structure of the MmpL3 of Mycobacterium tuberculosis using that of M. smegmatis as template. MmpL3 inhibitors, namely BM212, NITD304, SPIRO, and NITD349, in addition to the co-crystalized ligands AU1235, ICA38, SQ109 and rimonabant, were screened against the modelled structure and the Mmpl3 of M. smegmatis using molecular docking techniques. Protein-ligand interactions were analysed using molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann surface area computations. Novel residues Gln32, Leu165, Ile414, and Phe35 were identified as critical for binding to M. tuberculosis MmpL3, and conformational dynamics upon inhibitor binding were discussed.

Repurposing antiviral phytochemicals from the leaf extracts of Spondias mombin (Linn) towards the identification of potential SARSCOV-2 inhibitors.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a pneumonia-like disease with a pattern of acute respiratory symptoms, currently remains a significant public health concern causing tremendous human suffering. Although several approved vaccines exist, vaccine hesitancy, limited vaccine availability, high rate of viral mutation, and the absence of approved drugs account for the persistence of SARS-CoV-2 infections. The investigation of possibly repurposing of phytochemical compounds as therapeutic alternatives has gained momentum due to their reported affordability and minimal toxicity. This study investigated anti-viral phytochemical compounds from ethanolic leaf extracts of Spondias mombin L as potential inhibitor candidates against SARS-CoV-2. We identified Geraniin and 2-O-Caffeoyl-(+)-allohydroxycitric acid as potential SARS-CoV-2 inhibitor candidates targeting the SARS-CoV-2 RNA-dependent polymerase receptor-binding domain (RBD) of SARS-CoV-2 viral S-protein and the 3C-like main protease (3CLpro). Geraniin exhibited binding free energy (ΔGbind) of - 25.87 kcal/mol and - 21.74 kcal/mol towards SARS-CoV-2 RNA-dependent polymerase and receptor-binding domain (RBD) of SARS-CoV-2 viral S-protein respectively, whereas 2-O-Caffeoyl-(+)-allohydroxycitric acid exhibited a ΔGbind of - 32 kcal/mol towards 3CLpro. Molecular Dynamics simulations indicated a possible interference to the functioning of SARS-CoV-2 targets by the two identified inhibitors. However, further in vitro and in vivo evaluation of these potential SARS-CoV-2 therapeutic inhibitor candidates is needed.

Unravelling the Structural Mechanism of Action of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione in Dual-Targeting Tankyrase 1 and 2: A Novel Avenue in Cancer Therapy.

Tankyrase (TNKS) belonging to the poly(ADPribose) polymerase family, are known for their multi-functioning capabilities, and play an essential role in the Wnt ß-catenin pathway and various other cellular processes. Although showing inhibitory potential at a nanomolar level, the structural dual-inhibitory mechanism of the novel TNKS inhibitor, 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione, remains unexplored. By employing advanced molecular modeling, this study provides these insights. Results of sequence alignments of binding site residues identified conserved residues; GLY1185 and ILE1224 in TNKS-1 and PHE1035 and PRO1034 in TNKS-2 as crucial mediators of the dual binding mechanism of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione, corroborated by high per-residue energy contributions and consistent high-affinity interactions of these residues. Estimation of the binding free energy of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione showed estimated total energy of -43.88 kcal/mol and -30.79 kcal/mol towards TNKS-1 and 2, respectively, indicating favorable analogous dual binding as previously reported. Assessment of the conformational dynamics of TNKS-1 and 2 upon the binding of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione revealed similar structural changes characterized by increased flexibility and solvent assessible surface area of the residues inferring an analogous structural binding mechanism. Insights from this study show that peculiar, conserved residues are the driving force behind the dual inhibitory mechanism of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione and could aid in the design of novel dual inhibitors of TNKS-1 and 2 with improved therapeutic properties.

Novel Sunifiram-carbamate hybrids as potential dual acetylcholinesterase inhibitor and NMDAR co-agonist: simulation-guided analogue design and pharmacological screening.

An efficient method for synthesising NMDAR co-agonist Sunifiram (DM235), in addition to Sunifram-carbamate and anthranilamide hybrids, has been developed in high yields via protecting group-free stepwise unsymmetric diacylation of piperazine using N-acylbenzotiazole. Compounds 3f, 3d, and 3i exhibited promising nootropic activity by enhancing acetylecholine (ACh) release in A549 cell line. Moreover, the carbamate hybrid 3f was found to exhibit higher in vitro potency than donepezil with IC50 = 18 ± 0.2 nM, 29.9 ± 0.15 nM for 3f and donepezil, respectively. 3f was also found to effectively inhibit AChE activity in rat brain (AChE = 1.266 ng/mL) compared to tacrine (AChE = 1.137 ng/ml). An assessment of the ADMET properties revealed that compounds 3f, 3d, and 3i are drug-like and can penetrate blood-brain barrier. Findings presented here showcase highly potential cholinergic agents, with expected partial agonist activity towards glycine binding pocket of NMDAR which could lead to development and optimisation of novel nootropic drugs.

Conjugated Dienones from Differently Substituted Cinnamaldehyde as Highly Potent Monoamine Oxidase-B Inhibitors: Synthesis, Biochemistry, and Computational Chemistry.

Fifteen multiconjugated dienones (MK1-MK15) were synthesized and evaluated to determine their inhibitory activities against monoamine oxidases (MAOs) A and B. All derivatives were found to be potent and highly selective MAO-B inhibitors. Compound MK6, with an IC50 value of 2.82 nM, most effectively inhibited MAO-B, like MK12 (IC50 = 3.22 nM), followed by MK5, MK13, and MK14 (IC50 = 4.02, 4.24, and 4.89 nM, respectively). The selectivity index values of MK6 and MK12 for MAO-B over MAO-A were 7361.5 and 1780.5, respectively. Compounds MK6 and MK12 were competitive reversible inhibitors of MAO-B, with K i values of 1.10 ± 0.20 and 3.0 ± 0.27 nM, respectively. Cytotoxic studies showed that MK5, MK6, MK12, and MK14 exhibited low toxicities on Vero cells, with IC50 values of 218.4, 149.1, 99.96, and 162.3 µg/mL, respectively, which were much higher than those for their effective nanomolar-level concentrations. Also, MK5, MK6, MK12, and MK14 decreased cell damage in H2O2-induced cells via a significant scavenging effect of reactive oxygen species. Molecular modeling was performed to rationalize the potential inhibitory activities of MK5, MK6, MK12, and MK14 toward MAO-B and their possible binding mechanisms, showing high-affinity binding pocket interactions and conformation perturbations of the compounds with MAO-B, which were interpreted as the conformational dynamics of MAO-B. This study concluded that all the compounds tested were more potent MAO-B inhibitors than the reference drugs, and leading compounds could be further explored for their effectiveness in various kinds of neurodegenerative disorders.

Extended Double Bond Conjugation in the Chalcone Framework Favours MAO-B Inhibition: A Structural Perspective on Molecular Dynamics.

BACKGROUND: The monotropic membrane protein monoamine oxidase B (MAO-B) has been shown to be a crucial drug target for the treatment of neurodegenerative diseases. The design of recent inhibitor therapeutic agents of MAO-B involves conjugation and modification of a chalcone scaffold comprising two aryl or heteroaryl rings connected via a short spacer unit with rotatable bonds. Supported by experimental data, these modifications often result in high potent inhibitor compounds. METHODS: In this study, we employ molecular dynamics simulations to unravel the impact of extended double bond conjugation in two novel compounds, F1 and MO10, toward the inhibition of the MAO-B protein. It was revealed that extended double bond conjugation induced a unidirectional orientation and motion of F1 and MO10, suggesting a stable binding pocket anchorage favouring high-affinity pocket interactions. RESULTS: Conformational analyses also revealed that the incorporated double bond extension impeded the motion of individual binding pocket residues, which subsequently disrupted the functionality of MAO-B. DISCUSSION: Real-time structural dynamics also revealed that the extended double bond conjugation mediated peculiar interactions with MAO-B binding pocket residues characterized by π-alkyl, π-π stacking, and π-sulphur interactions which buried both compounds into the hydrophobic core of MAO-B and ultimately induced higher binding affinities of both F1 and MO10. CONCLUSION: These insights present useful structural perspectives of the extended double bond conjugation associated with the experimentally reported enhanced inhibitory activity of F1 and MO10 against MAO-B.

Mesembryanthemum tortuosum L. alkaloids modify anxiety-like behaviour in a zebrafish model.

ETHNOPHARMACOLOGICAL RELEVANCE: Mesembryanthemum tortuosum L. (previously known as Sceletium tortuosum (L.) N.E. Br.) is indigenous to South Africa and traditionally used to alleviate anxiety, stress and depression. Mesembrine and its alkaloid analogues such as mesembrenone, mesembrenol and mesembranol have been identified as the key compounds responsible for the reported effects on the central nervous system. AIM OF THE STUDY: To investigate M. tortuosum alkaloids for possible anxiolytic-like effects in the 5-dpf in vivo zebrafish model by assessing thigmotaxis and locomotor activity. MATERIALS AND METHODS: Locomotor activity and reverse-thigmotaxis, recognised anxiety-related behaviours in 5-days post fertilization zebrafish larvae, were analysed under simulated stressful conditions of alternating light-dark challenges. Cheminformatics screening and molecular docking were also performed to rationalize the inhibitory activity of the alkaloids on the serotonin reuptake transporter, the accepted primary mechanism of action of selective serotonin reuptake inhibitors. Mesembrine has been reported to have inhibitory effects on serotonin reuptake, with consequential anti-depressant and anxiolytic effects. RESULTS: All four alkaloids assessed decreased the anxiety-related behaviour of zebrafish larvae exposed to the light-dark challenge. Significant increases in the percentage of time spent in the central arena during the dark phase were also observed when larvae were exposed to the pure alkaloids (mesembrenone, mesembrenol, mesembrine and mesembrenol) compared to the control. However, mesembrenone and mesembranol demonstrated a greater anxiolytic-like effect than the other alkaloids. In addition to favourable pharmacokinetic and physicochemical properties revealed via in silico predictions, high-affinity interactions characterized the binding of the alkaloids with the serotonin transporter. CONCLUSIONS: M. tortuosum alkaloids demonstrated an anxiolytic-like effect in zebrafish larvae providing evidence for its traditional and modern day use as an anxiolytic.

Prioritizing the Catalytic Gatekeepers through Pan- Inhibitory Mechanism of Entrectinib against ALK, ROS1 and TRKA Tyrosine Kinases.

Despite the remarkable clinical activity of kinase inhibitors against anaplastic lymphoma kinase (ALK) and the closely related Ros1 and TRKA kinases, the emergence of resistance to these inhibitors often leads to relapse in most patients. Resistance is usually in the form of mutations and brain metastasis or inhibitors failing to penetrate the blood-brain barrier. The discovery of entrectinib has recently paved way for further exploration of kinase inhibitors that target ALK after it has reportedly demonstrated potency against ALK, Ros1, and TRKA kinases. However, the molecular mechanism surrounding its multi-targeting activity remains unresolved. As such, in this study, we investigate the pan-inhibitory mechanism of entrectinib towards ALK, Ros1, and TRKA, using in silico techniques. Findings show strong binding affinities of ALK = -40.92 kcal/mol, Ros1 = -36.60 kcal/mol, and TRKA = -45.99 kcal/mol for entrectinib towards ALK, Ros1, and TRKA, respectively. Pan-inhibitory binding of entrectinib is characterized by close interaction with peculiar gatekeeper residues on each tyrosine kinase. Entrectinib induced structural stability and rigidity in the backbone conformation of all three tyrosine kinases by showing a consistent pattern of structural alterations. These structural insights provided presents a baseline for the understanding of the pan-inhibitory activity of entrectinib. Establishing the cruciality of the interactions between the phenyl ring and gatekeeper residues could guide the structure-based design of novel tyrosine kinase inhibitors with improved therapeutic activities.

In silico screening of phytopolyphenolics for the identification of bioactive compounds as novel protease inhibitors effective against SARS-CoV-2.

Due to the unavailability specific drugs or vaccines (FDA approved) that can cure COVID-19, the development of potent antiviral drug candidates/therapeutic molecules against COVID-19 is urgently required. This study was aimed at in silico screening and study of polyphenolic phytochemical compounds in a rational way by virtual screening, molecular docking and molecular dynamics studies against SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) enzymes. The objective of the study was to identify plant-derived polyphenolic compounds and/or flavonoid molecules as possible antiviral agents with protease inhibitory potential against SARS-CoV-2. In this study, we report plant-derived polyphenolic compounds (including flavonoids) as novel protease inhibitors against SARS-CoV-2. From virtual docking and molecular docking study, 31 polyphenolic compounds were identified as active antiviral molecules possessing well-defined binding affinity with acceptable ADMET, toxicity and lead-like or drug-like properties. Six polyphenolic compounds, namely, enterodiol, taxifolin, eriodictyol, leucopelargonidin, morin and myricetin were found to exhibit remarkable binding affinities against the proteases with taxifolin and morin exhibiting the highest binding affinity toward Mpro and PLpro respectively. Molecular dynamics simulation studies of these compounds in complex with the proteases showed that the binding of the compounds is characterized by structural perturbations of the proteases suggesting their antiviral activities. These compounds can therefore be investigated further by in vivo and in vitro techniques to assess their potential efficacy against SARS-CoV-2 and thus serve as the starting point for the development of potent antiviral agents against the deadly COVID-19.

Dual-Inhibition of Human N-Myristoyltransferase Subtypes Halts Common Cold Pathogenesis: Atomistic Perspectives from the Case of IMP-1088.

The pharmacological inhibition of human N-myristoyltransferase (HsNMT) has emerged as an efficient strategy to completely prevent the replication process of rhinoviruses, a potential treatment for the common cold. This was corroborated by the recent discovery of compound IMP-1088, a novel inhibitor that demonstrated a dual-inhibitory activity against the two HsNMT subtypes 1 and 2 without inducing cytotoxicity. However, the molecular and structural basis for the dual-inhibitory potential of IMP-1088 has not been investigated. As such, we employ molecular modelling techniques to resolve the structural mechanisms that account for the dual-inhibitory prowess of IMP-1088. Sequence and nanosecond-based analyses identified Tyr296, Phe190, Tyr420, Leu453, Gln496, Val181, Leu474, Glu182, and Asn246 as residues common within the binding pockets of both HsNMT1 and HsNMT2 subtypes whose consistent interactions with IMP-1088 underpin the basis for its dual inhibitory potency. Nano-second-based assessment of interaction dynamics revealed that Tyr296 consistently elicited high-affinity π-π stacked interaction with IMP-1088, thus further highlighting its cruciality corroborating previous report. An exploration of resulting structural changes upon IMP-1088 binding further revealed a characteristic impeding of residue fluctuations, structural compactness, and a consequential burial of crucial hydrophobic residues, features required for HsNMT1/2 functionality. Findings present essential structural perspectives that augment previous experimental efforts and could also advance drug development for treating respiratory tract infections, especially those mediated by rhinoviruses.

Modelling the Transitioning of SARS-CoV-2 nsp3 and nsp4 Lumenal Regions towards a More Stable State on Complex Formation.

During coronavirus infection, three non-structural proteins, nsp3, nsp4, and nsp6, are of great importance as they induce the formation of double-membrane vesicles where the replication and transcription of viral gRNA takes place, and the interaction of nsp3 and nsp4 lumenal regions triggers membrane pairing. However, their structural states are not well-understood. We investigated the interactions between nsp3 and nsp4 by predicting the structures of their lumenal regions individually and in complex using AlphaFold2 as implemented in ColabFold. The ColabFold prediction accuracy of the nsp3-nsp4 complex was increased compared to nsp3 alone and nsp4 alone. All cysteine residues in both lumenal regions were modelled to be involved in intramolecular disulphide bonds. A linker region in the nsp4 lumenal region emerged as crucial for the interaction, transitioning to a structured state when predicted in complex. The key interactions modelled between nsp3 and nsp4 appeared stable when the transmembrane regions of nsp3 and nsp4 were added to the modelling either alone or together. While molecular dynamics simulations (MD) demonstrated that the proposed model of the nsp3 lumenal region on its own is not stable, key interactions between nsp and nsp4 in the proposed complex model appeared stable after MD. Together, these observations suggest that the interaction is robust to different modelling conditions. Understanding the functional importance of the nsp4 linker region may have implications for the targeting of double membrane vesicle formation in controlling coronavirus infection.

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.

Replacement of Chalcone-Ethers with Chalcone-Thioethers as Potent and Highly Selective Monoamine Oxidase-B Inhibitors and Their Protein-Ligand Interactions.

To develop new potent and highly selective MAO-B inhibitors from chalcone-thioethers, eleven chalcones-thioethers were synthesized and their monoamine oxidase (MAO) inhibition, kinetics, reversibility, and cytotoxicity of lead compounds were analyzed. Molecular dynamics were carried out to investigate the interactions. Compound TM8 showed potent inhibitory activity against MAO-B, with an IC50 value of 0.010 µM, followed by TM1, TM2, TM7, and TM10 (IC50 = 0.017, 0.021, 0.023, and 0.026 µM, respectively). Interestingly, TM8 had an extremely high selectivity index (SI; 4860) for MAO-B. Reversibility and kinetic experiments showed that TM8 and TM1 were reversible and competitive inhibitors of MAO-B with Ki values of 0.0031 ± 0.0013 and 0.011± 0.001 µM, respectively. Both TM1 and TM8 were non-toxic to Vero cells with IC50 values of 241.8 and 116.3 µg/mL (i.e., 947.7 and 402.4 µM), respectively, and at these IC50 values, both significantly reduced reactive oxygen species (ROS) levels. TM1 and TM8 showed high blood-brain barrier permeabilities in the parallel artificial membrane permeability assay. Molecular dynamics studies were conducted to investigate interactions between TM1 and TM8 and the active site of MAO-B. Conclusively, TM8 and TM1 are potent and highly selective MAO-B inhibitors with little toxicity and good ROS scavenging abilities and it is suggested that both are attractive prospective candidates for the treatment of neurological disorders.