Computer-Based Technologies for Virtual Screening and Analysis of Chemical Compounds Promising for Anti-HIV-1 Drug Desig
Computer-based technologies for in silico drug development comprising virtual screening, high-throughput docking, molecular dynamics simulations, and binding free energy calculations are presented. The efficiency of these technologies is demonstrated by t
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Institute of Bioorganic Chemistry NASB, 5/2 Academician Kuprevich street, 220141 Minsk, Belarus [email protected] 2 United Institute of Informatics Problems NASB, 6, Surganov street, 220012 Minsk, Belarus [email protected]
Abstract. Computer-based technologies for in silico drug development comprising virtual screening, high-throughput docking, molecular dynamics simulations, and binding free energy calculations are presented. The efficiency of these technologies is demonstrated by the identification of novel potential antiHIV-1 agents able to mimic pharmacophoric properties of potent and broad neutralizing antibodies 10e8, VRC01, and 3074 that target three different func‐ tionally conserved regions of the viral envelope proteins. Keywords: Virtual screening · Molecular docking · Molecular dynamics · Binding free energy calculations · HIV-1 entry inhibitors · Broadly neutralizing antibodies
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Introduction
To date, over twenty five drugs have been approved by the United States Food and Drug Administration for the treatment of HIV infection (reviewed in [1, 2]). These drugs are distributed into six major classes: (1) nucleoside-analog reverse transcriptase inhibitors, (2) non-nucleoside reverse transcriptase inhibitors, (3) protease inhibitors, (4) fusion inhibitors, (5) entry inhibitors, and (6) integrase inhibitors [1, 2]. The majority of these anti-HIV drugs belong to the inhibitors of reverse transcriptase and protease [1, 2]. These inhibitors act inside a target cell and cannot block the initial steps of the HIV-1 life cycle associated with virus entry. In this context, development of novel, potent and broadspectrum HIV-1 entry inhibitors is an area of considerable interest in the current antiHIV drug design and discovery. HIV-1 infection begins with virion entry into target cells through the interaction of viral envelope (Env) protein gp120 with primary receptor CD4 (reviewed in [3]). The binding of gp120 to CD4 induces the exposure of a second binding site for cellular coreceptor CCR5 or CXCR4 [3]. Following the binding, the gp41 transmembrane subunit of the Env protein undergoes a dramatic conformational change to mediate virus-cell © Springer International Publishing AG 2017 V.V. Krasnoproshin and S.V. Ablameyko (Eds.): PRIP 2016, CCIS 673, pp. 14–23, 2017. DOI: 10.1007/978-3-319-54220-1_2
Computer-Based Technologies for Virtual Screening and Analysis
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membrane fusion, enabling the virus capsid to enter the cell [3]. Many small molecule inhibitors that block the virus adsorption onto the host cell membrane and/or cell-medi‐ ated fusion have been developed [4]. However, the majority of these inhibitors have failed to be useful in clinical practice. Despite these disappointing results, the design of (+)-DMJ-I-228 and (+)-DMJ-II-121 inhibitors that target the Env trimer and present functional antagonists of viral entry [5] gave hope of future success in the development of novel efficient anti-HIV-1 drugs. This hope was supported by the discovery of antiHIV-1 broadly neutralizing antibodi
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