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A meta-analysis of Cryptosporidium species in humans from southern Africa (2000–2020)

Journal of Parasitic Diseases 2022年第1期46卷 304-316页

作者： Omolabi, Kehinde Foluke Odeniran, Paul Olalekan Soliman, Mahmoud E. Molecular Bio-Computation and Drug Design Laboratory School of Health Sciences University of KwaZulu-Natal Westville Campus Durban 4001 South Africa Department of Veterinary Parasitology and Entomology Faculty of Veterinary Medicine University of Ibadan Ibadan Nigeria

Abstract: The epidemiology of cryptosporidiosis in southern Africa is largely unknown. The disease is associated with diarrhea and nutritional deficiencies, leading to severe morbidity and mortality among immune-compromised patients. This study aimed to assess the pooled prevalence of Cryptosporidium spp. infection among immune-compromised humans in southern Africa over the past 20 years. Reports of Cryptosporidium spp. infection in humans published between 2000 and 2020 using Google Scholar, PubMed, Ovid Medline, African Journal Online (AJOL), and Web of Science literature databases were obtained. Inclusion criteria of sorted articles for Cryptosporidium spp. infection were standardized using preferred reporting items for systematic reviews and meta-analyses (PRISMA) checklist. A total of 22 eligible studies were sorted for meta-analysis. Overall prevalence of Cryptosporidium spp. infection in southern African countries with reports was 16.8% (95% CI 9.7–25.3). Sub-group analysis showed a pooled prevalence of 25.2, 20.5, and 17.9% among HIV/AIDS patients, children, and diarrhoeic individuals, respectively. Pooled prevalence was highest in South Africa and lowest in Zimbabwe across examined individuals. The pooled prevalence of Cryptosporidium spp. infections in diarrhoeic patients was highest in individuals from Botswana (17.6%) which is significantly different (Χ² = 9.337;P = 0.002) from South Africans (12.7%). South African individuals with HIV/AIDS showed the highest pooled prevalence of Cryptosporidium infections than other countries. The high prevalence of Cryptosporidium spp. infections among immune-compromised patients in southern Africa showed that the pathogen is of significant importance in this region. Continuous studies on the genetic characterization of Cryptosporidium spp. isolates and associated risk factors are needed across southern Africa to identify the predominant subtypes in humans. Graphic abstract: [Figure not available: see fullte

关键词： Cryptosporidiosis HIV Prevalence Protozoa Public health Zoonotic disease

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De Novo Rational design of peptide-based covalent inhibitors via mapping of complementary binding site residues – technical protocol and case study on KRASG12C and BTK481C

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BMC Methods 2025年第1期2卷 1-17页

作者： Oduro-Kwateng, Ernest Ali, Musab Kehinde, Ibrahim Oluwatobi Rao, Li Soliman, Mahmoud E. S. Molecular Bio-Computation and Drug Design Research Group School of Health Sciences University of KwaZulu Natal Durban South Africa State Key Laboratory of Green Pesticide College of Chemistry Central China Normal University Wuhan China

Targeting undruggable proteins and challenging binding sites, such as protein–protein interaction (PPI) interfaces and allosteric pockets, using small-molecule inhibitors is often infeasible. Peptide-based irreversible inhibitors are promising emerging strategies for the treatment of such targets. However, there is currently no systematic in silico protocol for the rational design of peptide-based covalent inhibitors. We developed a streamlined computational framework for the de novo design of peptide-based irreversible inhibitors. Key considerations include peptide sequence optimization for binding, selection of electrophilic warheads, peptide folding, target specificity, and pharmacokinetic and toxicity profiles. Binding affinities were estimated using covalent molecular dynamics (MDcov) simulations and thermodynamic binding free energy calculations. Using KRASG12C, a strategic drug target traditionally considered undruggable, as a case study, the protocol identified top-hit peptide inhibitors (RVKDX, HVKXR, and XLKDH) with binding free energies (BFEs) of -48.84, -48.93, and -48.67 kcal/mol, respectively. These values are comparable to sotorasib (-50.63 kcal/mol) and lower than adagrasib (-71.73 kcal/mol), both FDA-approved KRASG12C inhibitors. Benchmarking against BTK481C using zanubrutinib, an FDA-approved therapeutic agent for B-cell malignancies, further validated the protocol. Peptide inhibitors XDYMA, XDYVL, and QDWXL demonstrated BFEs of -83.40, -76.69, and -62.40 kcal/mol, outperforming zanubrutinib (-57.00 kcal/mol), acalabrutinib (-54.19 kcal/mol), and ibrutinib (-55.09 kcal/mol). These findings underscore the robustness and adaptability of our protocol, offering a systematic, multifaceted approach that can be integrated into drug discovery workflows to design novel peptide-based irreversible inhibitors.

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Establishing the mutational effect on the binding susceptibility of AMG510 to KRAS switch II binding pocket: computational insights

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Informatics in Medicine Unlocked 2022年 30卷

作者： Issahaku, Abdul Rashid Aljoundi, Aimen Soliman, Mahmoud E.S. Molecular Bio-computation and Drug Design Laboratory School of Health Sciences University of KwaZulu-Natal Westville Campus Durban 4001 South Africa

After decades of leaving patients with limited treatment options due to the ‘undruggability’ of Kirsten rat sarcoma, the kernel was finally cracked with the discovery of Sotorasib. This novel drug binds to a small pocket on the switch II of Kirsten rat sarcoma by exploiting the mutation that occurs at codon 12 wherein glycine is replaced by cysteine. However, this pocket is not only prone to cysteine mutation but other mutations occur as well including at codon 13. These mutations have been reported to drive cancer in the lungs, colorectal and in solid tumors with varying degree of expressions. Sotorasib is therefore only effective in a small group of patients especially those expressing cysteine at codon 12, reminding drug hunters of the unfinished work. This study employs computational techniques to understand the susceptibility of the mutated binding pocket to the binding of Sotorasib. It was revealed that the binding affinity of Sotorasib to other mutations aside Cysteine was significantly affected via the total free binding energies presented by the mutated complexes. Furthermore, the quantum of energy contributed by the mutated residues except cysteine was significantly reduced suggesting the binding of Sotorasib is enhanced in only cysteine mutated Kirsten rat sarcoma. Residual interaction network showed Sotorasib in complex with the cysteine mutated protein presented the highest degree centrality, shortest path betweenness, shortest path centrality and shortest path degree indicating Sotorasib controls more information flow within the cysteine mutated protein than in other mutations. Insight unraveled here will provide aid in the development of pan Kirsten rat sarcoma inhibitory small molecules. © 2022 The Authors

关键词： AMG510 KRAS Protein KRASG12C MMPBSA Mutations Residue interaction network

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Highlighting the mechanistic role of Olutasidenib (FT-2102) in the selective inhibition of mutated isocitrate dehydrogenase 1 (mIDH1) in cancer therapy

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Informatics in Medicine Unlocked 2022年 28卷

作者： Salifu, Elliasu Y. Agoni, Clement Soliman, Mahmoud E.S. Molecular Bio-computation and Drug Design Lab School of Health Sciences University of KwaZulu-Natal Westville Campus Durban 4001 South Africa

Mutations in isocitrate dehydrogenase enzymes 1 and 2 (mIDH1/2) results in an aberrant accumulation of (R)-2-hydroxyglutarate (2-HG), excess of which has been shown to inhibit alpha ketoglutarate (αKG)-dependent enzymes leading to the development of gliomas. Inhibition of mutant IDH1 has therefore been evaluated clinically as a treatment option for gliomas. Recently, Olutasidenib (FT-2102), was discovered as a highly potent and selective inhibitor of mIDH1. However, the mechanistic activities surrounding its selective inhibitory potency remain unclear. Herein, this study provides the structural and mechanistic insights that underpin the reported selectivity of FT-2102 on mDH1 using molecular dynamic (MD) simulations and advanced post-MD analysing techniques. Findings revealed that the selectivity of FT-2102 towards mIDH1 is mediated by high-affinity interactions with residues Arg109, Ile128 and Val281 within the binding pocket. Also, a unidirectional orientation of FT-2102 within mIDH1 anchored by the high-affinity interactions accounted for its higher stability and stronger binding of −56.82 kcal/mol relative to lower binding affinity of −14.48 kcal/mol towards mIDH2. Furthermore, the binding of FT-2102 in mIDH1 conferred more stability at the binding pocket which resulted in maintenance of crucial atomic interactions as compared to mIDH2 where binding was characterized by inconsistency and loss of crucial interactions. These findings thus present a detailed insight into the selective inhibitory mechanism of FT-2102 towards mIDH1 and could aid in the design and development of novel mutant IDH inhibitors. © The Authors

关键词： Binding affinity Dual-inhibition Isocitrate dehydrogenase 1 and 2 molecular dynamic simulation Mutation Olutasidenib

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Disrupting the characteristic twist motion;tailored in silico approach towards the design of plasmepsin inhibitors

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Informatics in Medicine Unlocked 2022年 33卷

作者： Kumi, Ransford Oduro Yakubu, Elliasu Salifu Agoni, Clement Bidemi, Akawa Oluwole Soliman, Mahmoud E.S. Molecular Bio-computation and Drug Design Laboratory School of Health Sciences University of KwaZulu-Natal Westville Campus Durban 4001 South Africa Takoradi Technical University Department of Industrial and Health Sciences Main Campus Takoradi Ghana

The effort to eradicate malaria has not yet been achieved, and the parasitic infection remains a global challenge. The burden stems from the worldwide dissemination of parasites resistant to commonly used chemotherapeutics and the scarcity of the malaria vaccine, Mosquirix. In the quest to augment malaria treatment, current focus has been geared towards plasmepsin (P). These classes of aspartic acid proteases are expressed at multiple stages of the parasite's life cycle and are implicated in host haemoglobin degradation and parasite dissemination in vivo;elaborating their essentiality as therapeutic targets. Our earlier research examined the structural dynamics of WM382, a novel antimalarial compound, in relation to its enzyme inhibitory mechanism on plasmepsin IX (PMIX) and plasmepsin X (PMX). WM382 inflicts structural compactness on both proteases. The pharmacophoric moieties of WM382 were used in the present study to search the Zinc database for WM382 derivatives. The leads, ZINC06868602, ZINC09431717 and ZINC13367223 formed strong intermolecular bonds with the catalytic dyad Asp32 and Asp281. The flap regions generally move away from the binding pocket, divulging the active site to the inhibitor and keeping it near to the catalytic dyad. However, upon binding of the leads, the flap residues wrapped inward to surround the inhibitors, further restricting the characteristic twist motion of these proteases for enzyme activity. Likewise, for the experimental drug candidate WM382, the identified leads displayed high affinity for PMIX, with total binding free energies of leads estimated to be −33.45 kcal/mol, −30.33 kcal/mol and −29.67 kcal/mol, respectively. Evaluation of per residue energy composition indicated the catalytic dyad contributes immensely towards ligand binding. Results from our study suggest these compounds have better inhibitory prowess against PMIX. The potency of these chemicals should further be tested in the experimental laboratory to evaluate thei

关键词： Malaria Pharmacophore model Plasmepsin Virtual screening WM382

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Ethno-medicinal, phytochemistry, and pharmacological importance of Hunteria umbellate (K. Schum.) Hallier f. (Apocynaceae): a useful medicinal plant of sub-Saharan Africa

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Clinical Phytoscience 2021年第1期7卷 1-17页

作者： Fadahunsi, Olumide Samuel Adegbola, Peter Ifeoluwa Olorunnisola, Olubukola Sinbad Subair, Temitayo Idris Adepoju, David Oluwasegun Abijo, Ayodeji Zabdiel Department of Biochemistry Ladoke Akintola University of Technology Ogbomoso Nigeria Molecular Bio-computation and Drug Design Laboratory School College of Health Sciences University of KwaZulu-Natal Durban South Africa Department of Anatomy Ladoke Akintola University of Technology Ogbomoso Nigeria

Hunteria umbellate (K. Schum.) Hallier f. (Apocynaceae) is a tropical rainforest tree commonly found in sub-Saharan region of Africa. It is a useful and very popular plant among the locals due to the outstanding anti-diabetic activity of the seeds. A comprehensive literature search on articles published on phytochemical analysis and various pharmacological activities of Hunteria umbellate was carried out using search engines such as Google Scholar, PubMed and Science Direct. In this review, it was deduced that H. umbellate is employed in folk medicine as an elixir for obesity, fever, leprosy sores, menstrual pain, infertility, yaws, intestinal worms, abdominal discomfort and stomach ache. Due to their durability and immunity against termites, the stems are coveted and desired as timbers in the construction of houses, while the bark has been reportedly exported to Europe for medicinal uses. Pharmacological activities such as fertility enhancing, aphrodisiac, hypoglycemic, anti-inflammatory, has been ascribed to the different morphological organs of H. umbellate. Moreover, compounds belonging to important classes of secondary metabolites with biological activities such as triterpenoids, flavonoids, tannins, alkaloids, quinic acids have been identified and characterized from the plant. From this review, it can be inferred that, numerous and bioactive principles with known biological usefulness are present in the extracts of H. umbellate and might be responsible for the observed biological and pharmacological activities.

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The Characteristic Structural and Functional Dynamics of P. Falciparum Dhfr Binding with Pyrimidine Chemotypes Implicate Malaria Therapy design

SSRN

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SSRN 2024年

作者： Mosebi, Salerwe Oluyemi, Wande M. Nwokebu, Goodness Adewumi, Adeniyi T. Eze, Shadrach C. Mbachu, Chinedu C. Ogueli, Emmanuel C. Nwodo, Ngozi Soliman, Mahmoud E.S. Department of Pharmaceutical and Medicinal Chemistry College of Pharmacy Afe Babalola University Ekiti State Ado-Ekiti Nigeria Department of Pharmaceutical Chemistry Faculty of Pharmaceutical Sciences University of Nigeria Nsukka Nigeria Department of Life and Consumer Sciences University of South Africa Calabash Building Room 02-026 Johannesburg South Africa University of KwaZulu-Natal Medical School Campus South Africa Molecular Bio-computation and Drug Design Laboratory School of Health Sciences University of KwaZulu-Natal Westville Campus Durban4001 South Africa

Dihydrofolate reductase (DHFR) enzyme regulates de-novo folate synthesis in Plasmodium falciparum, hence considered a critical malaria drug target. Pyrimethamine inhibits DHFR, but resistance and lack of cross-species activity are its challenges. Therefore, investigating more potent nitrogenous heterocyclic compounds against DHFR is critical in this study. Docking and MD simulations were employed to gain insight into the 500 screened compounds’ binding free energies and conformational stabilities of the final four, and cross-species activity was determined using sequence alignment. Several screening criteria were used to narrow the chemical space, including the highest binding affinity to pfDHFR and molecules satisfying drug-likeness properties like Lipinski’s RO5 and ADMET. PMD_01 (-12.2 kcal/mol), PMD_02 (-11.1 kcal/mol), PMD_03 (-10.7 kcal/mol), and PMD_04 (-10.7 kcal/mol) have the highest binding affinities against pfDHFR among proposed inhibitors compared to pyrimethamine (-7.9 kcal/mol). pfDHFR’s active site Leu45, Thr107, Ile164, and Thr170 were crucial for binding interactions. PMD-bound systems showed higher binding free energy than pyrimethamine, except PMD_03. Hydrogen bonding interactions with Gly159, Ser101, Ser104, Ser160, Ile157, and Lys48 played significant roles in the binding interaction of these compounds as opposed to Asp53 in pyrimethamine. The four systems attained stabilities around 1.90 Å RMSD and showed more stability than pyrimethamine-bound and unbound pfDHFR. The pocket’s residues across the four plasmodia were highly conserved, but Phe116 and Ile164 replaced Met in P. knowlesi and Tyr in the other species. PMD_01, PMD_02, PMD_03, and PMD_04 showed promising inhibition against pfDHFR and are, thus, potential antimalarial agents against plasmodia DHFR homologues subject to experimental validation. © 2024, The Authors. All rights reserved.

关键词： Hydrogen bonds

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Dual enzymatic inhibitory mechanism of WM382 on plasmepsin IX and X: Atomistic perspectives from dynamic analysis

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Informatics in Medicine Unlocked 2022年 29卷

作者： Kumi, Ransford O. Agoni, Clement Ibrahim, Mahmoud A.A. Soliman, Mahmoud E.S. Molecular Bio-computation and Drug Design Laboratory School of Health Sciences University of KwaZulu-Natal Westville Campus Durban 4001 South Africa Takoradi Technical University (TTU) Department of Industrial and Health Sciences Main Campus Takoradi Ghana CompChem Lab Chemistry Department Faculty of Science Minia University Minia 61519 Egypt

The unprecedented occurrence of malaria and the increase rate of parasite resistance to current therapeutics have over the past decade elicited researchers’ interest in probing novel drug targets and unabatedly searching for competitive inhibitors. Plasmepsin (PM) family of aspartic proteases has recently been at the forefront in this pursuit to augment malaria treatment. In malaria infections engineered by P. falciparum, PMIX and PMX are highlighted as mediators of egress, invasion and spread of the infection in humans. Despite these proteases' druggability, there is currently no authorized inhibitor. WM382, a small molecule inhibitor, has been demonstrated to have dual inhibitory properties against both proteases, which is promising. However, the structural dynamics associated with the dual inhibition mechanism remain unclear. As such, we employed integrative computer-assisted atomistic techniques to provide thorough structural dynamic insights. The binding WM382 confers structural stability on both proteases through a mesh of hydrogen and hydrophobic interactions with binding site residues. The overall binding energies of PMIX and PMX were estimated to be −27.27 kcal/mol and −23.95 kcal/mol respectively, however, the trademark aspartic acid residues in the binding pocket of these proteases contributed minimally to this effect. WM382 increased structural flexibility creating excessively loose conformation that distorts the characteristic “twist motion” of the members of the plasmepsin family. These assimilated conformations further affect the biological role of both proteases. Energy decomposition analysis proved that Phe77/Phe75 contributed significantly to the overall binding of WM382 within the binding pockets of both PMIX and PMX eliciting strong intermolecular interactions, thus favouring binding affinity. The stable orientations of WM382 within the respective hydrophobic pockets allowed favorable interactions with binding site residues which accounted for it

关键词： Malaria chemotherapy molecular dynamic simulation Plasmepsin WM382

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Apigenin attenuates depressive-like behavior via modulating monoamine oxidase A enzyme activity in chronically stressed mice

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Current Research in Pharmacology and drug Discovery 2023年 5卷 100161页

作者： Olayinka, Juliet N. Akawa, Oluwole B. Ogbu, Emmanuela K. Eduviere, Anthony T. Ozolua, Raymond I. Soliman, Mahmoud Neuropharmacology Unit Department of Pharmacology and Therapeutics College of Medicine and Health Sciences Afe Babalola University P.M.B. 5454 Ekiti State Ado-Ekiti Nigeria Molecular Bio-computation and Drug Design Laboratory Discipline of Pharmaceutical Chemistry University of Kwazulu-Natal South Africa Department of Pharmacology and Toxicology Faculty of Pharmacy University of Benin Benin City 300001 Nigeria Department of Pharmacology Faculty of Basic Medical Sciences Delta State University Delta State Abraka Nigeria

Chronic stress is a risk factor for depression and is characterized by elevated levels of brain monoamine oxidase A (MAOA). Mounting evidence has shown that MAOA is a biochemical link between stress and depression. Apigenin (API), a natural flavonoid, as demonstrated in vitro inhibitory effect on MAOA, is suggestive of antidepressant-like activity. However, the in vivo inhibitory effect of API on MAOA and how it affects depression still remain unclear. Here, we report the probable mechanisms of action of API in chronic unpredictable mild stress (CUMS)-induced depression in mice. Treatment with API reversed anhedonia, and reduced anxiety and immobility time in behavioral studies. API reduced brain corticosterone and malondialdehyde (MDA) levels but increased brain levels of glutathione and superoxide dismutase. Furthermore, interleukin-6 and tumor necrosis factor-α were attenuated by API. It also restored cell loss and inhibited the activity of MAOA in the hippocampal brain regions and prefrontal cortex. Comparative binding affinity of API for MAOA (-7.7 kcal/mol) through molecular docking studies was greater than that of reference compound, clorgyline (-6.8 kcal/mol). Favorable hydrophobic interactions important to API binding at MAOA binding cavity was revealed to include conventional hydrogen bond (Cys323 and Tyr444), π-Sulfur (Cys323), π-π Stacked (Tyr407), π-π T-shaped (Phe208), π-lone pair and π-alkyl (Ile335, Ile180) interactions. These results suggest that API is a potent, selective, reversible inhibitor of MAOA with capability of attenuating CUMS-induced depression via inhibiting MAOA enzyme activity and altering other pathomechanisms. © 2023

关键词： Apigenin Chronic unpredictable mild stress Depression molecular docking Monoamine oxidase A enzyme

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Identification and classification of differentially expressed genes reveal potential molecular signature associated with SARS-CoV-2 infection in lung adenocarcinomal cells

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Informatics in Medicine Unlocked 2020年 20卷 100384-100384页

作者： Soremekun, Opeyemi S. Omolabi, Kehinde F. Soliman, Mahmoud E.S. Molecular Bio-computation and Drug Design Laboratory School of Health Sciences University of KwaZulu-Natal Westville Campus Durban 4001 South Africa

Genomic techniques such as next-generation sequencing and microarrays have facilitated the identification and classification of molecular signatures inherent in cells upon viral infection, for possible therapeutic targets. Therefore, in this study, we performed a differential gene expression analysis, pathway enrichment analysis, and gene ontology on RNAseq data obtained from SARS-CoV-2 infected A549 cells. Differential expression analysis revealed that 753 genes were up-regulated while 746 down-regulated. SNORA81, OAS2, SYCP2, LOC100506985, and SNORD35B are the top 5 upregulated genes upon SARS-Cov-2 infection. Expectedly, these genes have been implicated in the immune response to viral assaults. In the Ontology of protein classification, a high percentage of the genes are classified as Gene-specific transcriptional regulator, metabolite interconversion enzyme, and Protein modifying enzymes. Twenty pathways with P-value lower than 0.05 were enriched in the up-regulated genes while 18 pathways are enriched in the down-regulated DEGs. The toll-like receptor signalling pathway is one of the major pathways enriched. This pathway plays an important role in the innate immune system by identifying the pathogen-associated molecular signature emanating from various microorganisms. Taken together, our results present a novel understanding of genes and corresponding pathways upon SARS-Cov-2 infection, and could facilitate the identification of novel therapeutic targets and biomarkers in the treatment of COVID-19. © 2020

关键词： COVID-19 Differentially expressed genes Enrichment analysis RNAseq SARS-CoV-2

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