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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.

Introduction: Alzheimer's disease (AD) is an intensifying neurodegenerative illness due to its irreversible nature. Identification of β‐site amyloid precursor protein (APP) cleaving enzyme1 (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. Method: 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 potential BACE1 inhibitors with a significant outcome. The most used computer-aided approach in BACE1 inhibitor design and binding/interaction studies are pharmacophore development, quantitative structure-activity relationship (QSAR), virtual screening, docking, and molecular dynamics (MD) simulations. These methods, plus more advanced ones including quantum mechanics/molecular mechanics (QM/MM) and QM, have proven substantial in the computational framework 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 compounds, 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 design. 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 strategy. 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.

: Over decades of its identification, numerous past and ongoing researches have focused on the therapeutic roles of β-amyloid cleaving enzyme 1 (BACE1) as a target in treating Alzheimer's disease (AD). Although the initial BACE1 inhibitors at phase-3 clinical trials tremendously reduced β-amyloid-associated plaques in patients with AD, the researchers eventually discontinued the tests due to the 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 to 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 sites 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.