Pocket-Based Drug Design: Exploring Pocket Space

Zheng, Xiliang; Gan, Linfeng; Wang, Erkang; Wang, Jin

doi:10.1208/s12248-012-9426-6

Cited by 73 publications

(59 citation statements)

References 91 publications

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“…Binding sites in target proteins can be experimentally determined; for example using site-directed mutagenesis or X-ray crystallography. There are also a variety of computational binding pocket identifying algorithms available for the drug discovery scientific community [87]. …”

Section: Reviewmentioning

confidence: 99%

Computational methods in drug discovery

Leelananda

Lindert

2016

Beilstein J. Org. Chem.

479

309

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The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD) tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeutic development. The human genome project has made available a substantial amount of sequence data that can be used in various drug discovery projects. Additionally, increasing knowledge of biological structures, as well as increasing computer power have made it possible to use computational methods effectively in various phases of the drug discovery and development pipeline. The importance of in silico tools is greater than ever before and has advanced pharmaceutical research. Here we present an overview of computational methods used in different facets of drug discovery and highlight some of the recent successes. In this review, both structure-based and ligand-based drug discovery methods are discussed. Advances in virtual high-throughput screening, protein structure prediction methods, protein–ligand docking, pharmacophore modeling and QSAR techniques are reviewed.

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Section: Reviewmentioning

confidence: 99%

Computational methods in drug discovery

Leelananda

Lindert

2016

Beilstein J. Org. Chem.

479

309

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“…However, the large moiety of the drug molecule is exposed to the lipid environment (e.g., Figure 3C left and 3D left). The receptor in this region is very shallow, without any obvious cavity that could be used for rational drug design [37]. Regarding helix flexibility, a number of experimental and simulation studies showed that increased regional flexibility was in fact caused by the presence of proline residue in the transmembrane region [38,39].…”

Section: Allosteric Sites Next To Ecl2 Tm3 and Tm4 Helicesmentioning

confidence: 99%

New Binding Sites, New Opportunities for GPCR Drug Discovery

Chan

Dahoun

et al. 2019

Trends in Biochemical Sciences

113

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Many central biological events rely on protein-ligand interactions. The identification and characterization of protein-binding sites for ligands are crucial for the understanding of functions of both endogenous ligands and synthetic drug molecules. G protein-coupled receptors (GPCRs) typically detect extracellular signal molecules on the cell surface and transfer these chemical signals across the membrane, inducing downstream cellular responses via G proteins or b-arrestin. GPCRs mediate many central physiological processes, making them important targets for modern drug discovery. Here, we focus on the most recent breakthroughs in finding new binding sites and binding modes of GPCRs and their potentials for the development of new medicines. The Classical Orthosteric Ligand-Binding Site G protein-coupled receptors (GPCRs; see Glossary) play an essential role in many physiological processes, including vision, olfaction and sense of smell, neuronal signal transmission, cell differentiation, pain, muscle contraction, and hormone secretion, to name a few [1-4]. Thus, GPCRs are among the most important targets for modern medicines (Box 1) [5]. Identifying the ligand-binding sites in target GPCRs is the first important step in a structure-based drug development process [6,7]. Recent progress in illuminating structures of GPCRs show that, besides binding to the traditional orthosteric site, ligands could also bind to remote allosteric sites (Table 1) which provide many new opportunities for drug discovery [7-12]. The traditional orthosteric site (Figure 1A) of GPCRs is close to the extracellular region of receptors, between a highly conserved W 6.48Â48 in transmembrane helix 6 (TM6) and extracellular loop 2 (ECL2). To define the relative position of each amino acid in a TM region, the generic residue numbering methods have been introduced for GPCRs (Box 2) [13]. Most residues (Figure 1B) frequently interacting with orthosteric ligands are in TM3 (positions 3.28

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“…There are various site detection 16 and pocket search 17 (PS) methods available to accomplish this task. [20] SiteHound-web online server was used in the present study to discover the pocket. In SiteHound grid, maps are calculated for the probes covering the entire proteins with 1 and 0.9 A° spacing, respectively.…”

Section: Pocket Findingmentioning

confidence: 99%

Untitled

Soni¹

2017

AJP

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Aim: Mycobacterium tuberculosis (TB) is the causative agent of tuberculosis (TB) and is responsible for more than eight million new infections worldwide and about two million deaths each year. New chemotherapeutics are required to treat the emerging threat of multidrug-resistant and extensively drug-resistant strains. Materials and Methods: Microarray data analysis techniques used to find novel gene target. In the present study, it was found that four novel genes named as MetZ (amino acid biosynthesis), aceAB (respiration system), relE (virulence activity), and kdaP (cell transport system) can be targeted that are inclusive of unique and important function in cell metabolism of organism. Discontinuing the function of these genes might kill the mycobacterium and prominently the specified relE gene, which plays a significant role in virulence effect, by inhibiting this gene, an individual with TB can be saved from TB disease if diagnosed and prognosis will be done at an early stage. Pharmacophore techniques are used in the present study to screen out lacs of molecule. Molecules downloaded from ZINC database are run through pharmacophore screening and docking procedure. Results: Finally, it was observed that top five (on the bases of binding energy) molecules from docking procedure gave improved result in ADME and toxicity analysis.

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Pocket-Based Drug Design: Exploring Pocket Space

Cited by 73 publications

References 91 publications

Computational methods in drug discovery

Computational methods in drug discovery

New Binding Sites, New Opportunities for GPCR Drug Discovery

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