The use of vaccinations and antiviral medications have gained popularity in the therapeutic management of avian influenza H7N9 virus lately. Antiviral medicines are more popular due to being readily available. The presence of the neuraminidase protein in the avian influenza H7N9 virus and its critical role in the cleavage of sialic acid have made it a target drug in the development of influenza virus drugs. Generally, the neuraminidase proteins have common conserved amino acid residues and any mutation that occurs around or within these conserved residues affects the susceptibility and replicability of the influenza H7N9 virus. Herein, we investigated the interatomic and intermolecular dynamic impacts of the experimentally reported E119V mutation on the oseltamivir resistance of the influenza H7N9 virus. We extensively employed molecular dynamic (MD) simulations and subsequent post-MD analyses to investigate the binding mechanisms of oseltamivir-neuraminidase wildtype and E119V mutant complexes. The results revealed that the oseltamivir-wildtype complex was more thermodynamically stable than the oseltamivir-E119V mutant complex. Oseltamivir exhibited a greater binding affinity for wildtype (−15.46 ± 0.23 kcal/mol) relative to the E119V mutant (−11.72 ± 0.21 kcal/mol). The decrease in binding affinity (−3.74 kcal/mol) was consistent with RMSD, RMSF, SASA, PCA, and hydrogen bonding profiles, confirming that the E119V mutation conferred lower conformational stability and weaker protein–ligand interactions. The findings of this oseltamivir-E119V mutation may further assist in the design of compounds to overcome E119V mutation in the treatment of influenza H7N9 virus patients.
Background The overuse of prescribed antimicrobials, concurrent use of traditional medicine, and prescribed antimicrobials have led to antimicrobial resistance. The absence of collaboration between traditional health practitioners and biomedically trained healthcare professionals can contribute to antimicrobial resistance, treatment failure, overdose, toxicity, and misadministration. This scoping review explores the evidence on collaboration between traditional health practitioners and biomedically trained healthcare professionals to reduce antimicrobial resistance and treatment failure in bacterial and viral diseases. Methods We will search for electronic databases such as Science Direct, Google Scholar, PubMed, and MEDLINE via EBSCOhost. We will also search reference lists of included studies. A two-stage mapping procedure will be carried out. Stage one (1) will consist of the title, abstracts, and full article screening, respectively. A pilot screening form guided by the defined eligibility criteria will be used. In stage two (2), data will be extracted from the included studies. Two reviewers will conduct parallel screening and data extraction. Mixed methods appraisal tool (MMAT) will be used to assess the quality of the included studies. NVIVO version 11 will be employed to aid pertinent thematic analysis. The outcomes of interest will be as follows: Primary outcome will be preventing and reducing antimicrobial resistance. The secondary effect is the effective collaboration between traditional healthcare practitioners and biomedically healthcare professionals. Discussion This review anticipates uncovering pertinent publications reporting the evidence of collaboration between traditional health practitioners and biomedically trained healthcare professionals to reduce antimicrobial resistance in sub-Saharan Africa. The sum-up of evidence acquired from the included studies will help guide future research. The result of the study will be print and electronically exposed. Systematic review registration PROSPERO, CRD42017072952
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for COVID-19, which was declared a global pandemic in March 2020 by the World Health Organization (WHO). Since SARS-CoV-2 main protease plays an essential role in the virus’s life cycle, the design of small drug molecules with lower molecular weight has been a promising development targeting its inhibition. Herein, we evaluated the novel peptidomimetic azatripeptide and azatetrapeptide nitriles against SARS-CoV-2 main protease. We employed molecular dynamics (MD) simulations to elucidate the selected compounds’ binding free energy profiles against SARS-CoV-2 and further unveil the residues responsible for the drug-binding properties. Compound 8 exhibited the highest binding free energy of −49.37 ± 0.15 kcal/mol, followed by compound 7 (−39.83 ± 0.19 kcal/mol), while compound 17 showed the lowest binding free energy (−23.54 ± 0.19 kcal/mol). In addition, the absorption, distribution, metabolism, and excretion (ADME) assessment was performed and revealed that only compound 17 met the drug-likeness parameters and exhibited high pharmacokinetics to inhibit CYP1A2, CYP2C19, and CYP2C9 with better absorption potential and blood-brain barrier permeability (BBB) index. The additional intermolecular evaluations suggested compound 8 as a promising drug candidate for inhibiting SARS-CoV-2 Mpro. The substitution of isopropane in compound 7 with an aromatic benzene ring in compound 8 significantly enhanced the drug’s ability to bind better at the active site of the SARS-CoV-2 Mpro.
In over a century since its discovery, Alzheimer’s disease (AD) has continued to be a global health concern due to its incurable nature and overwhelming increase among older people. In this paper, we give an overview of the efforts of researchers towards identifying potent BACE1 exosite-binding antibodies and allosteric inhibitors. Herein, we apply computer-aided drug design (CADD) methods to unravel the interactions of some proposed psychotic and meroterpenoid BACE1 allosteric site inhibitors. This study is aimed at validating the allosteric potentials of these selected compounds targeted at BACE1 inhibition. Molecular docking, molecular dynamic (MD) simulations, and post-MD analyses are carried out on these selected compounds, which have been experimentally proven to exhibit allosteric inhibition on BACE1. The SwissDock software enabled us to identify more than five druggable pockets on the BACE1 structural surface using docking. Besides the active site region, a melatonin derivative (compound 1) previously proposed as a BACE1 allostery inhibitor showed appreciable stability at eight different subsites on BACE1. Refinement with molecular dynamic (MD) simulations shows that the identified non-catalytic sites are potential allostery sites for compound 1. The allostery and binding mechanism of the selected potent inhibitors show that the smaller the molecule, the easier the attachment to several enzyme regions. This finding hereby establishes that most of these selected compounds failed to exhibit strong allosteric binding with BACE1 except for compound 1. We hereby suggest that further studies and additional identification/validation of other BACE1 allosteric compounds be done. Furthermore, this additional allosteric site investigation will help in reducing the associated challenges with designing BACE1 inhibitors while exploring the opportunities in the design of allosteric BACE1 inhibitors.
Background Schistosomiasis is one of the most prevalent parasitic diseases in low- and middle-income countries (LMICs), being regarded as a neglected tropical disease in sub-Saharan Africa. Praziquantel is the conventional treatment recommended for schistosomiasis in mainstream healthcare systems. In many poor settings, while many people reportedly use both traditional medicine and public sector mainstream healthcare systems, little is known if those infected with schistosomiasis use both African traditional and prescribed antischistosomal medicines. This review aims to map evidence of the concomitant management of schistosomiasis by traditional health practitioners (THPs) and health care professionals (HCPs) in communities with a high prevalence schistosomiasis infection in LMICs. Methods/design Guided by Arksey and O’Malley scoping review framework and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), we will map the evidence from relevant studies dating from 2007 to 2019 published in LMICs. An electronic keyword search of the following databases will be conducted: PubMed, Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and MEDLINE via EBSCOhost, Google Scholar, and WILEY online Library. Peer-reviewed articles, gray literature sources, and reference lists will be included to identify eligible studies. Following title screening, two reviewers will independently screen the abstracts and full texts. Any study that focuses on managing schistosomiasis will be included. The data will be analyzed using thematic analysis with the help of NVIVO software version 12, with the Mixed Method Appraisal Tool (MMAT) being used to assess the quality of the included studies. Discussion This review will map the evidence in the literature of the concomitant management of schistosomiasis by THPs and HCPs in communities with a high prevalent infection in LMICs. The review findings will be important for policy makers across the healthcare continuum and be used to inform stakeholders’ consensus process to explore the development of a generic set of patient-centered quality indicators that are applicable to multiple care settings. It will also identify research gaps in schistosomiasis management in LMICs and provide direction for future research. The results will be disseminated through a peer-reviewed publication and presented in relevant conferences. Systematic review registration PROSPERO CRD42017078198 Electronic supplementary material The online version of this article (10.1186/s13643-019-1088-3) contains supplementary material, which is available to authorized users.
The H7N9 virus attaches itself to the human cell receptor protein containing the polysaccharide that terminates with sialic acid. The mutation of neuraminidase at residue E119 has been explored experimentally. However, there is no adequate information on the substitution with E119V in peramivir at the intermolecular level. Therefore, a good knowledge of the interatomic interactions is a prerequisite in understanding its transmission mode and subsequent effective inhibitions of the sialic acid receptor cleavage by neuraminidase. Herein, we investigated the mechanism and dynamism on the susceptibility of the E119V mutation on the peramivir–neuraminidase complex relative to the wildtype complex at the intermolecular level. This study aims to investigate the impact of the 119V substitution on the neuraminidase–peramivir complex and unveil the residues responsible for the complex conformations. We employed molecular dynamic (MD) simulations and extensive post-MD analyses in the study. These extensive computational investigations were carried out on the wildtype and the E119V mutant complex of the protein for holistic insights in unveiling the effects of this mutation on the binding affinity and the conformational terrain of peramivir–neuraminidase E119V mutation. The calculated total binding energy (ΔGbind) for the peramivir wildtype is −49.09 ± 0.13 kcal/mol, while the E119V mutant is −58.55 ± 0.15 kcal/mol. The increase in binding energy (9.46 kcal/mol) is consistent with other post-MD analyses results, confirming that E119V substitution confers a higher degree of stability on the protein complex. This study promises to proffer contributory insight and additional knowledge that would enhance future drug designs and help in the fight targeted at controlling the avian influenza H7N9 virus. Therefore, we suggest that experimentalists collaborate with computational chemists for all investigations of this topic, as we have done in our previous studies.
COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly in the search for drug candidates that interact with various SARS-CoV-2 receptors. These studies involve the use of computer simulations and computational algorithms to predict the potential interaction of drug candidates with target receptors. The primary receptors targeted by drug candidates include the RNA polymerase, main protease, spike protein, ACE2 receptor, TMPRSS2, and AP2-associated protein kinase 1. In silico studies have identified several promising drug candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, and Camostat mesylate, among others. The use of in silico studies offers several advantages, including the ability to screen a large number of drug candidates in a relatively short amount of time, thereby reducing the time and cost involved in traditional drug discovery methods. Additionally, in silico studies allow for the prediction of the binding affinity of drug candidates to target receptors, providing insight into their potential efficacy. However, it is crucial to consider both the advantages and limitations of these studies and to complement them with experimental validation to ensure the efficacy and safety of identified drug candidates.
Background Worldwide, Human Immunodeficiency Virus / Acquired Immunodeficiency Syndrome (HIV/AIDS) remains a public health problem. The prevalence of HIV in Sub-Saharan Africa is one of the uppermost in the world. Method/design Observational studies will be systematically reviewed reporting on morbidity and mortality in the antiretroviral therapy (ART) era in Sub-Saharan Africa. We will search relevant studies from the following databases: PubMed, Medline, CINAHL. Two review authors will independently screen titles abstracts and full text articles in duplicate, extract data and assess the bias. Discrepancies will be resolved by discussion or arbitration of a third review author. The study will use the Preferred Reporting Item of Systematic Review (PRISMA 2015) guideline. Discussion This review will summarise the determinants of morbidity and causes of mortality in the antiretroviral era in Sub-Saharan Africa. The findings of this study will help to improve opportunistic infection’s prevention and clinical outcomes in ART era. Systematic review registration PROSPERO CDR42019141933
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