Toluwase Hezekiah Fatoki

Benign prostatic hypertrophy (BPH) is a prevalent condition affecting the prostate gland of elderly men. This study investigated the effects of H. sabdariffa leaf flavonoid extracts on BPH induction in rats. Thirty-six male Wistar rats were split into six groups: normal controls, BPH-induced rats (3 mg/kg testosterone), and rats treated with BPH-induced with flavonoid extract (300 mg/kg and 150 mg/kg) or a standard drug (1 mg/kg finasteride). After 28 days, biochemical, histological, and molecular parameters were assessed. The extract rich in flavonoids from H. sabdariffa markedly (p < 0.05) decreased the amount of MDA and enhanced the activities of antioxidant enzymes in rats administered with BPH. The extracts substantially attenuated inflammatory markers such as IL-6, IL-1β, and TNFα levels. Histological examination revealed improved prostate architecture in the treated groups in contrast to those in BPH-induced rats. Additionally, substantial (p < 0.05) downregulation of CEA, AKT, MMP9, and PSA in the extract-treated groups was observed. HPLC characterization identified prominent flavonoids, with quercetin being the most abundant bioactive compound. The outcome of this study proffers the therapeutic activities of H. sabdariffa flavonoid extract on BPH rat model.

Malaria, a life-threatening disease caused by Plasmodium parasites, remains a major global health concern, with 247 million cases and approximately 627,000 deaths reported in 2020 across 84 malaria-endemic countries. The Plasmodium falciparum P-type ATPase 4 (PfATP4) gene is expressed throughout the parasite's asexual erythrocytic cycle and plays a vital role in regulating sodium ion levels in the plasma membrane. This study aimed to computationally evaluate selected clinical candidate compounds targeting PfATP4, focusing on their pharmacokinetics and molecular binding characteristics to support further drug development. Pharmacokinetic analyses revealed that Concanamycin A, Maduramicin, and GNF-Pf4492 exhibit low gastrointestinal absorption, while Brefeldin A, MMV396719, MMV006239, and Cipargamin can cross the blood-brain barrier. Among these, Brefeldin A and MMV006239 showed the lowest toxicity. Molecular docking revealed that (+)-SJ733 had the highest binding affinity (-8.891 kcal/mol), followed by MMV665878 (-7.796 kcal/mol) and Maduramicin (-7.791 kcal/mol). All 11 compounds showed binding affinities below -7.000 kcal/mol. Molecular dynamics simulations indicated stable interactions between PfATP4 and both (+)-SJ733 and MMV665878, involving key residues such as PHE917, GLN921, ARG985, and THR993. MMGBSA analysis showed that the MMV665878-PfATP4 complex was more stable and energetically favorable than the (+)-SJ733-PfATP4 complex under simulated physiological conditions. In conclusion, (+)-SJ733 and MMV665878 demonstrate strong potential as PfATP4 inhibitors, with different interaction profiles. Further in vivo and pharmacometric studies are required to validate their efficacy and determine optimal dosing strategies for malaria treatment.

Oritavancin is a semi-synthetic lipoglycopeptide antibiotic primarily used to treat serious infections caused by Gram-positive bacteria. The aim of this study was to elucidate possible molecular targets of oritavancin in human and microbes in relevance to its mechanism of action and model its pharmacokinetics for optimal dose selection in clinical practice. Computational methods were used in this study which include target prediction, molecular docking, molecular dynamics simulation, pharmacokinetics prediction, and physiological-based pharmacokinetics (PBPK) modeling. Oritavancin was moderately soluble in water and did not permeate the blood-brain barrier. Seven molecular targets were identified in humans. Molecular docking results showed highest binding affinity of oritavancin with PI3-kinase p110-gamma subunit (−10.34 kcal/mol), followed by Acyl-CoA desaturase (−10.07 kcal/mol) and Cytochrome P450 2C19 (−8.384 kcal/mol). Oritavancin PBPK modelling in adult human showed that infusion has lower peak concentrations (Cmax) compared to bolus administration, with 1200 mg dose yielded Cmax of 16.559 mg/L, 800 mg dose yielded Cmax of 11.258 mg/L, and 200 mg over 3 days dose yielded Cmax of 7.526 mg/L. Notably, infusion gave extended half-life (t1/2) for all doses and slightly higher clearance rates compared to bolus, particularly for the 1200 mg and 800 mg doses. The results corroborated existing clinical pharmacokinetic data, and confirmed the model’s accuracy and predictive capability. This comprehensive computational study has provided invaluable insights into the pharmacological profile of Oritavancin, aiding its further development and optimization for clinical use.

Lobelia inflata is a remarkable member of the Lobelia family, and it possesses diverse therapeutic properties such as anticancer, anti-neurodegenerative and antimicrobial effects. This study aimed to computationally explore the pharmacological potential of L. inflata phytochemicals. The methods used are pharmacokinetic predictions, target predictions, gene network analysis, molecular docking and molecular dynamics (MD) simulation. The findings revealed that all phytoconstituents have blood-brain barrier (BBB) permeability and high gastrointestinal absorption (GIA). Synaptic vesicular amine transporter 2 (VMAT2) and ceramide transfer protein (CERT) emerged as key human molecular targets of these phytoconstituents. The binding affinity of lobelanidine and norlobelanine for CERT was −9.027 kcal ⋅ mol[ ] and −7.537 kcal ⋅ mol[ ] respectively, while (+)-lobinaline and lobeline have binding affinity of −6.897 kcal ⋅ mol[ ] and −6.724 kcal ⋅ mol[ ],[ ] respectively for VMAT2. MD simulation and molecular mechanics/generalized Born surface area (MMGBSA) calculations highlighted the stability and energetically favorable nature of the lobelanidine-VMAT2 and Lobelanidine-CERT complexes. This study underscores the potential of L. inflata in modulating CERT and VMAT2 targets in cancer and neurodegenerative diseases, respectively. There is a need for further validation of these results through additional research endeavors.

Introduction: Erectile dysfunction (ED) which is the inability to maintain an erection during sexual activity, is one of the most prevalent sexual dysfunctions, with mild to severe ED affecting an estimated 5-20% of men globally and about 322 million men may be affected globally by 2025. Aim: The present study was carried out to explore the phenolic constituents of Pentaclethra macrophylla, its antioxidant properties and potential binding mechanism on the key proteins linked to erectile dysfunction. Method: The method used included phytochemical screening, high-performance liquid chromatography coupled with diode array detector (HPLC-DAD) quantification, in vitro analyses as well as in silico analyses such as target prediction, molecular docking and molecular dynamics (MD) simulation. Results: The phytochemical screening revealed that the extract contains various phytochemicals such as alkaloids, flavonoids, tannins, saponins and terpenoids. The total flavonoid and total phenolic contents were increased with increasing concentrations of the extract while DPPH and nitric oxide percentage scavenged activities were not significantly changed across the concentrations. The chromatogram of the phenolic contents of P. macrophyla obtained from HPLC-DAD indicated the presence of major compounds such as naringin, ellagic acid, epicatechin, epigallocatechin gallate, quercetin, myricetin, and rutin. The results of the target prediction showed that compounds relevant to ED are naringin, kaempferol, quercetin, and myricetin. Molecular docking results indicated that they have affinity for myeloperoxidase, followed by phosphodiesterase 5 (PDE5) and acetylcholinesterase. Naringin has the highest binding affinity (-11.040 kcal.mol ^-1 ) for myeloperoxidase, and 9.333 kcal.mol ^-1 for PDE5. The results of MDS indicate changes in the binding energy and stability of the complex of PDE5 with naringin as well as myeloperoxidase with naringin. Conclusion: Overall, the results proposed naringin as the potential bioactive compound in P. macrophylla that could be useful for treatment of erectile dysfunction.

Amyotrophic lateral sclerosis (ALS) is a complex, multi-system disorder characterized by glial cell involvement, immune system dysfunction, axonal transport disturbances, and impaired mitochondrial and neurotrophic support. Developing a specialised database for the efficient screening and identification of potential anti-ALS compounds is essential for advancing therapeutic discovery. This study presents the design and development of OTPD4ALS (Open Targets Potential Drugs for ALS), a comprehensive database specifically tailored to accelerate the identification of promising drug candidates. The methodology involved curating potential compounds, predicting pharmacokinetics in batches, and structuring the database for optimal accessibility. OTPD4ALS provides a streamlined platform for quickly identifying potential therapeutic compounds and is publicly available at https://otpd4als.vercel.app.

Amyotrophic lateral sclerosis (ALS) is a fatal, currently incurable neurodegenerative disease that progressively affects the upper motor neurons in the brain and lower motor neurons in the spinal cord. A significant portion of patients exhibit abnormalities in lipid metabolism, which appear to contribute to denervation and subsequent motor neuron degeneration. This study aimed to computationally identify lipid-based compounds associated with ALS and elucidate their pathological and therapeutic roles to facilitate effective ALS diagnosis and treatment. The methodologies employed encompassed rational database searches, pharmacokinetic and target predictions, as well as docking and molecular dynamics simulations (MDS). The findings from the disease-to-lipids analysis identified 20 lipid compounds correlated with ALS, primarily categorized as potential inhibitors within the functional classes of vitamins, antibiotics, organic acids, and phytochemicals. Pharmacokinetic predictions revealed that only four compounds exhibited permeability across the blood–brain barrier, namely 4-hydroxynonenal, resveratrol, rotenone, and valproic acid. Docking simulations indicated the highest binding affinity for 4-hydroxynonenal with alkaline ceramidase 2 (−4.516 kcal/mol), resveratrol with carbonic anhydrase 6 (−7.070 kcal/mol), rotenone with cytochrome P450 2C19 (−7.378 kcal/mol), and valproic acid with glutamate carboxypeptidase 2 (−5.629 kcal/mol). Furthermore, MDS and molecular mechanics/generalized born surface area calculations demonstrated the stability and binding energies of the complexes under simulated physiological conditions. In summary, further investigation is warranted to explore the synergistic effects of resveratrol and valproic acid in ALS, the mechanisms underlying 4-hydroxynonenal adduct-assisted aggregate formation of certain enzymes in ALS, and the impact of prolonged human exposure to rotenone from marine food sources (such as fish) on the development of ALS.

Cymbopogon citratus (DC) Stapf. is utilized in both culinary and medicinal contexts, wherein its extracts demonstrate a range of therapeutic properties, including antidiabetic, antioxidant, and anti-inflammatory activities. This investigation aimed to computationally analyze phytochemicals of C. citratus, evaluating their pharmacokinetics and binding dynamics. The findings revealed a combination of high and low gastrointestinal absorption (GIA) for C. citratus (DC.) phytochemicals, with some exhibiting permeability across the blood-brain barrier (BBB). Xanthine dehydrogenase/oxidase (XDH) emerged as the primary human molecular target of C. citratus phytocompounds, while XDH and matrix metalloproteinase-9 (MMP9) have central connectivity in the protein interaction network. Orientin has best binding affinity with XDH (−9.083 kcal.mol−1) and MMP9 (−9.051 kcal.mol−1). Molecular dynamic simulations indicated the favorable stability and interactions of XDH with orientin and quercetin, respectively. In summary, this investigation underscores the potential of twenty-six (26) phytochemicals in C. citratus extract to combat cancer and neurodegenerative diseases through mechanisms targeting XDH and MMP9. Received: 27 February 2024 | Revised: 31 May 2024 | Accepted: 14 June 2024 Conflicts of Interest The authors declare that they have no conflicts of interest to this work. Data Availability Statement The SwissADME data that support the findings of this study are openly available at www.swissadme.ch, reference number [11]. The SEA Search data that support the findings of this study are openly available at www.sea.bkslab.org, reference number [12]. The STRING data that support the findings of this study are openly available at https://string-db.org, reference number [13]. The eXpression2Kinases data that support the findings of this study are openly available at https://maayanlab.cloud/X2K/, reference number [14]. The UniProt data that support the findings of this study are openly available at www.uniprot.org.

Superoxide dismutase 1 (SOD1), a copper-dependent enzyme, facilitates the conversion of superoxide anions into hydrogen peroxide and oxygen, thereby regulating superoxide levels. Dysfunctions in SOD1 have been linked to neurodegenerative disorders such as amyotrophic lateral sclerosis, as well as liver and lung cancers. This study aimed to identify SOD1 modulators using in silico rational virtual enrichment screening, pharmacokinetics, docking, and molecular dynamic simulation (MDS). The findings yielded 38 compounds, predominantly exhibiting high gastrointestinal absorption but mostly non-permeable across the blood–brain barrier, with few exhibiting inhibitory effects on selected cytochrome P450s. Molecular docking revealed that compound 1 (PubChem CID: 36791369) exhibited the highest binding affinity (−6.771 kcal·mol-1), followed by compound 19 (PubChem CID: 30935) with −6.468 kcal·mol-1, and compound 20 (PubChem CID: 135744521) with −5.978 kcal·mol-1. MDS and molecular mechanics/generalized Born surface area analysis indicated that the compound CID 36791369 – SOD1 complex and compound CID 30935 – SOD1 complex remained stable and energetically favorable under simulated physiological conditions at 0 ns and 100 ns. In conclusion, this study identified 38 compounds, among which compounds SN5, SN6, SN7, SN12, and SN25 emerged as potential inhibitors of SOD1 based on overall analyses. Further, research will be necessary to investigate the therapeutic effectiveness of these top five compounds in vitro and in vivo against SOD1.