Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation.

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.

Allostery Inhibition of BACE1 by Psychotic and Meroterpenoid Drugs in Alzheimer's Disease Therapy.

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.

Structural Investigations and Binding Mechanisms of Oseltamivir Drug Resistance Conferred by the E119V Mutation in Influenza H7N9 Virus.

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.

Heat Shock Protein 90 (HSP90) Inhibitors as Anticancer Medicines: A Review on the Computer-Aided Drug Discovery Approaches over the Past Five Years.

Cancer is a disease caused by the uncontrolled, abnormal growth of cells in different anatomic sites. In 2018, it was predicted that the worldwide cancer burden would rise to 18.1 million new cases and 9.6 million deaths. Anticancer compounds, often known as chemotherapeutic medicines, have gained much interest in recent cancer research. These medicines work through various biological processes in targeting cells at various stages of the cell's life cycle. One of the most significant roadblocks to developing anticancer drugs is that traditional chemotherapy affects normal cells and cancer cells, resulting in substantial side effects. Recently, advancements in new drug development methodologies and the prediction of the targeted interatomic and intermolecular ligand interaction sites have been beneficial. This has prompted further research into developing and discovering novel chemical species as preferred therapeutic compounds against specific cancer types. Identifying new drug molecules with high selectivity and specificity for cancer is a prerequisite in the treatment and management of the disease. The overexpression of HSP90 occurs in patients with cancer, and the HSP90 triggers unstable harmful kinase functions, which enhance carcinogenesis. Therefore, the development of potent HSP90 inhibitors with high selectivity and specificity becomes very imperative. The activities of HSP90 as chaperones and cochaperones are complex due to the conformational dynamism, and this could be one of the reasons why no HSP90 drugs have made it beyond the clinical trials. Nevertheless, HSP90 modulations appear to be preferred due to the competitive inhibition of the targeted N-terminal adenosine triphosphate pocket. This study, therefore, presents an overview of the various computational models implored in the development of HSP90 inhibitors as anticancer medicines. We hereby suggest an extensive investigation of advanced computational modelling of the three different domains of HSP90 for potent, effective inhibitor design with minimal off-target effects.

Intermolecular Mechanism and Dynamic Investigation of Avian Influenza H7N9 Virus' Susceptibility to E119V-Substituted Peramivir-Neuraminidase Complex.

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.

Impact of the R292K Mutation on Influenza A (H7N9) Virus Resistance towards Peramivir: A Molecular Dynamics Perspective.

In March 2013, a novel avian influenza A (H7N9) virus emerged in China. By March 2021, it had infected more than 1500 people, raising concerns regarding its epidemic potential. Similar to the highly pathogenic H5N1 virus, the H7N9 virus causes severe pneumonia and acute respiratory distress syndrome in most patients. Moreover, genetic analysis showed that this avian H7N9 virus carries human adaptation markers in the hemagglutinin and polymerase basic 2 (PB2) genes associated with cross-species transmissibility. Clinical studies showed that a single mutation, neuraminidase (NA) R292K (N2 numbering), induces resistance to peramivir in the highly pathogenic H7N9 influenza A viruses. Therefore, to evaluate the risk for human public health and understand the possible source of drug resistance, we assessed the impact of the NA-R292K mutation on avian H7N9 virus resistance towards peramivir using various molecular dynamics approaches. We observed that the single point mutation led to a distorted peramivir orientation in the enzyme active site which, in turn, perturbed the inhibitor's binding. The R292K mutation induced a decrease in the interaction among neighboring amino acid residues when compared to its wild-type counterpart, as shown by the high degree of fluctuations in the radius of gyration. MM/GBSA calculations revealed that the mutation caused a decrease in the drug binding affinity by 17.28 kcal/mol when compared to the that for the wild-type enzyme. The mutation caused a distortion of hydrogen bond-mediated interactions with peramivir and increased the accessibility of water molecules around the K292 mutated residue.

An Overview of ß-Amyloid Cleaving Enzyme 1 (BACE1) in Alzheimer's Disease Therapy: Elucidating its Exosite-Binding Antibody and Allosteric Inhibitor.

Over decades of its identification, numerous past and ongoing research has focused on ß- amyloid cleaving enzyme 1 (BACE1) therapeutic roles as a target in treating Alzheimer's disease (AD). Although the initial BACE1 inhibitors at phase-3 clinical trials tremendously reduced ß -amyloidassociated plaques in patients with AD, the researchers eventually discontinued the tests for lack of potency. This discontinuation has resulted in limited drug development and discovery targeted at BACE1, despite the high demand for dementia and AD therapies. It is, therefore, imperative to describe the detailed underlying biological basis of the BACE1 therapeutic option in neurological diseases. Herein, we highlight BACE1 bioactivity, genetic properties, and role in neurodegenerative therapy. We review research contributions on BACE1 exosite-binding antibody and allosteric inhibitor development as AD therapies. The review also covers BACE1 biological function, the disease-associated mechanisms, and the enzyme conditions for amyloid precursor protein site splitting. Based on the present review, we suggest further studies on anti-BACE1 exosite antibodies and BACE1 allosteric inhibitors. Non-active site inhibition might be the way forward to BACE1 therapy in Alzheimer's neurological disorder.

Alzheimer's Disease and ß-secretase Inhibition: An Update with a Focus on Computer-aided Inhibitor Design.

INTRODUCTION: Alzheimer's disease (AD) is an intensifying neurodegenerative illness due to its irreversible nature. Identification of ß-site Amyloid Precursor Protein (APP) cleaving en-zyme1 (BACE1) has been a significant medicinal focus towards AD treatment, and this has opened ground for several investigations. Despite the numerous works in this direction, no BACE1 inhibitor has made it to the final approval stage as an anti-AD drug. METHODS: We provide an introductory background of the subject with a general overview of the pathogenesis of AD. The review features BACE1 inhibitor design and development with a focus on some clinical trials and discontinued drugs. Using the topical keywords BACE1, inhibitor design, and computational/theoretical study in the Web of Science and Scopus database, we retrieved over 49 relevant articles. The search years are from 2010 and 2020, with analysis conducted from May 2020 to March 2021. RESULTS AND DISCUSSION: Researchers have employed computational methodologies to unravel po-tential BACE1 inhibitors with a significant outcome. The most used computer-aided approach in BACE1 inhibitor design and binding/interaction studies are pharmacophore development, quantita-tive structure-activity relationship (QSAR), virtual screening, docking, and molecular dynamics (MD) simulations. These methods, plus more advanced ones including quantum mechan-ics/molecular mechanics (QM/MM) and QM, have proven substantial in the computational frame-work for BACE1 inhibitor design. Computational chemists have embraced the incorporation of in vitro assay to provide insight into the inhibition performance of identified molecules with potential inhibition towards BACE1. Significant IC50 values up to 50 nM, better than clinical trial com-pounds, are available in the literature. CONCLUSION: The continuous failure of potent BACE1 inhibitors at clinical trials is attracting many queries prompting researchers to investigate newer concepts necessary for effective inhibitor de-sign. The considered properties for efficient BACE1 inhibitor design seem enormous and require thorough scrutiny. Lately, researchers noticed that besides appreciable binding affinity and Blood-Brain Barrier (BBB) permeation, BACE1 inhibitor must show low or no affinity for permeability-glycoprotein. Computational modeling methods have profound applications in drug discovery strat-egies. With the volume of recent in silico studies on BACE1 inhibition, the prospect of identifying potent molecules that would reach the approved level is feasible. Investigators should try pushing many of the identified BACE1 compounds with significant anti-AD properties to preclinical and clinical trial stages. We also advise computational research on allosteric inhibitor design, exosite modeling, and multisite inhibition of BACE1. These alternatives might be a solution to BACE1 drug discovery in AD therapy.

Unravelling the molecular basis of AM-6494 high potency at BACE1 in Alzheimer's disease: an integrated dynamic interaction investigation.

ß-amyloid precursor protein cleaving enzyme1 (BACE1) has prominently been an important drug design target implicated in Alzheimer's disease pathway. The failure rate of most of the already tested drugs at different clinical phases remains a major concern. Recently, AM-6494 was reported as a novel potent, highly selective, and orally effective inhibitor against BACE1. AM-6494 displayed no alteration of skin/fur colour in animal studies, an adverse effect common to previous BACE1 inhibitors. However, the atomistic molecular mechanism of BACE1 inhibition by AM-6494 remains unclear. To elucidate the binding mechanism of AM-6494 relative to umibecestat (CNP-520) as well as the structural changes when bound to BACE1, advanced computational techniques such as accelerated MD simulation and principal component analysis have been utilised. The results demonstrated higher binding affinity of AM-6494 at BACE1 with van der Waals as dominant energy contributor compared to umibecestat. Conformational monitoring of the ß-hairpin flap covering the active site revealed an effective flap closure when bound with AM-6494 compared to CNP-520, which predominantly alternates between semi-open and closed conformations. The observed effective flap closure of AM-6494 explains its higher inhibitory power towards BACE1. Besides the catalytic Asp32/228 dyad, Tyr14, Leu30, Tyr71 and Gly230 represent critical residues in the potency of these inhibitors at BACE1 binding interface. The findings highlighted in this research provide a basis to explain AM-6494 high inhibitory potency and might assist in the design of new inhibitors with improved selectivity and potency for BACE1.

Computational modelling of potent ß-secretase (BACE1) inhibitors towards Alzheimer's disease treatment.

Researchers have identified the ß-amyloid precursor protein cleaving enzyme 1 (BACE1) in the multifactorial pathway of Alzheimer's disease (AD) as a drug target. The design and development of molecules to inhibit BACE1 as a potential cure for AD thus remained significant. Herein, we simulated two potent BACE1 inhibitors (AM-6494 and CNP-520) to understand their binding affinity at the atomistic level. AM-6494 is a newly reported potent BACE1 inhibitor with an IC50 value of 0.4 nM in vivo and now picked for preclinical considerations. Umibecestat (CNP-520), which was discontinued at human trials lately, was considered to enable a reasonable evaluation of our results. Using density functional theory (DFT) and Our Own N-layered Integrated molecular Orbital and Molecular Mechanics (ONIOM), we achieved the aim of this investigation. These computational approaches enabled the prediction of the electronic properties of AM-6494 and CNP-520 plus their binding energies when complexed with BACE1. For AM-6494 and CNP-520 interaction with protonated BACE1, the ONIOM calculation gave binding free energy of -62.849 and -33.463 kcal/mol, respectively. In the unprotonated model, we observed binding free energy of -59.758 kcal/mol in AM-6494. Taken together thermochemistry of the process and molecular interaction plot, AM-6494 is more favourable than CNP-520 towards the inhibition of BACE1. The protonated model gave slightly better binding energy than the unprotonated form. However, both models could sufficiently describe ligand binding to BACE1 at the atomistic level. Understanding the detailed molecular interaction of these inhibitors could serve as a basis for pharmacophore exploration towards improved inhibitor design.