Drug repositioning by structure-based virtual screening

Ma, Dik‐Lung; Chan, Daniel Shiu‐Hin; Leung, Chung‐Hang

doi:10.1039/c2cs35357a

Cited by 202 publications

(152 citation statements)

References 115 publications

(111 reference statements)

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“…Polyene (13) is isolated from the network; it is not commonly combined with other chemoyls. Flavones ( 1 ), steroids ( 7 ), alkaloids ( 14 ) and terpenes ( 15 ) are most frequently (indicated by darker lines) present in natural products simultaneously, so as to exhibit more bioactivities.…”

Section: Resultsmentioning

confidence: 99%

Drug Discovery Inspired by Mother Nature: Seeking Natural Biochemotypes and the Natural Assembly Rules of the Biochemome

Yan

2013

J Pharm Pharm Sci

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Purpose. The Human Genome Project is producing a new biological ‘periodic table’, which defines all genes for making macromolecules (proteins, DNA, RNA, etc) and the relations between genes and their biological functions. We now need to consider whether to initiate a biochemome project aimed at discovering biochemistry’s ‘periodic table’, which would define all molecular parts for making small molecules (natural products) and the relations between the parts and their functions to regulate genes. By understanding the Biochemome, we might be able to design biofunctional molecules based upon a set of molecular parts for drug innovation. Methods. A number of algorithms for processing chemical structures are used to systematically derive chemoyls (natural building blocks) from a database of compounds identified in Traditional Chinese Medicine (TCM). The rules to combine chemoyls for biological activities are then deduced by mining an annotated TCM structure-activity database (ATCMD). Based upon the rules and the basic chemoyls, a chemical library can be biochemically profiled, virtual synthetic routes can be planned, and lead compounds can be identified for a specific drug target. Conclusions. The Biochemome is the complete set of molecular components (chemoyls) in an organism and Biochemomics studies the rules governing their assembly and their evolution, together with the relations between the Biochemome and drug targets. This approach provides a new paradigm for drug discovery that is based on a comprehensive knowledge of the synthetic origins of biochemical diversity, and helps to direct biomimetic syntheses aimed at assembling quasi-natural product libraries for drug screening. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Section: Resultsmentioning

confidence: 99%

Drug Discovery Inspired by Mother Nature: Seeking Natural Biochemotypes and the Natural Assembly Rules of the Biochemome

Yan

2013

J Pharm Pharm Sci

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“…The possibility of repositioning existing drugs for new indications is particularly attractive since it potentially reduces the expensive costs associated with hit compounds in early-stage tests. 62 In this way, optimization of the compounds identified in this study could yield potent DGC inhibitors harboring drug-like properties with the potential to counteract biofilm-based chronic infections.…”

Section: Functional Tests On the Selected Compounds From The Virtual mentioning

confidence: 99%

Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases

Wiggers¹,

Crusca²,

Silva³

et al. 2017

J. Braz. Chem. Soc.

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Biofilms are widely present in many human chronic infections, often more resistant to treatment with antibiotics. Bacterial diguanylate cyclases (DGCs) synthesize cyclic dimeric guanosine monophosphate (c-di-GMP) from two guanosine-5'-triphosphate (GTP) molecules. c-di-GMP is a central second messenger controlling biofilm formation, turning this class of enzymes an attractive target to prevent and disrupt biofilms of pathogenic bacteria. Here, we apply an in silico ligand-and target-based hybrid method to screen potential DGC inhibitors from an FDA-approved drug databank. Mass spectrometry assays confirmed that seven screened compounds selectively bound to the GTP active site of P. aeruginosa WspR GGDEF domain. Four out of those, including the anti-inflammatory sulfasalazine and the anti-hypertensive eprosartan, inhibited distinct DGCs (P. aeruginosa WspR and E. coli YdeH) in the micromolar range. Sulfasalazine and eprosartan reduced aggregation in solution of E. coli overexpressing WspR or YdeH. Similar anti-aggregation effects were also observed for sulfasalazine-related anti-inflammatory drugs sulfadiazine and sulfathiazole, the latter a previously described anti-biofilm agent. The optimized pharmacokinetic properties and toxicological profiles of the DGC inhibitors could be promising candidates for new anti-microbial agents based on the drug reposition strategy.Keywords: c-di-GMP, diguanylate cyclase enzymes, bacterial biofilm, virtual screening, drug repositioning IntroductionBacterial biofilms, a multicellular community encased in an extracellular matrix, are commonly related to persistent infections, usually less susceptible to antibiotic treatments when compared to planktonic cells. [1][2][3] According to the National Institute of Health, 4 up to 80% of human bacterial infections involve biofilm-associated microorganisms. For instance, biofilm formation plays a crucial role in microbe pathogenicity such as Legionnaire's disease, endocarditis, pneumonia accompanied by cystic fibrosis and infections of urogenital and gastrointestinal tracts. 5,6 Furthermore, biofilm infections promote devastating effects on medical device implanted and immunocompromised individuals, representing a major medical and economic predicament. 7 The burden on public health due to chronic biofilm contaminations urge for the development of new chemotherapeutic approaches. Cellular processes controlling biofilm formation and dispersion, such as quorum sensing systems and metabolic pathways, are important targets for the discovery of new bioactive compounds. 8-10The second messenger bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) is a key regulator of bacterial behavior, especially controlling the switch between the motile planktonic and sedentary biofilm-associated lifestyles. Cyclic di-GMP stimulates the biosynthesis of adhesins and exopolysaccharide matrix substances in biofilms and inhibits various forms of motility. In general, low intracellular c-di-GMP levels are associated with freeswimming cells, whereas bacter...

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“…FeCl 3 -induced arterial thrombosis model BALB/c mice were anesthetized subcutaneously with xylazin (16 mg kg 1 ) and ketamine (100 mg kg -1 ). The right common carotid artery was isolated via a midline cervical incision, and the blood flow was monitored continuously using a Transonic Systems 0.5VB doppler flow probe coupled to a Transonic Systems TS420 flowmeter, as described previously.…”

Section: 73mentioning

confidence: 99%

“…1 The drug discovery and development pathway from a novel drug target to a Food and Drug Administration (FDA) approved drug and to the marketing of a novel molecular entity is long and expensive, which prompts new pharmaceutical companies and laboratories to benefit from the usage of computational methods. 2,3 Computational methods now play an integral role in understanding intermolecular interactions and although algorithms are based on approximations and assumptions, molecular modeling has become the leading tool in modern drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Pyrazolyl-Tetrazoles and Imidazolyl-Pyrazoles as Potential Anticoagulants and their Integrated Multiplex Analysis Virtual Screening

Lourenço

Vegi

Faria

et al. 2018

J. Braz. Chem. Soc.

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This article reports a novel virtual screening algorithm seeking the rational identification of novel lead anticoagulants. Seven 5-(3-methyl-1-aryl-1H-pyrazol-4-yl)-1H-tetrazoles and seven novel 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-3-methyl-1H-pyrazoles were obtained in three steps starting from arylhydrazine hydrochlorides as raw materials in good yields: 50-72% and 50-85%, respectively. All compounds were submitted to an in silico target-base pipeline named integrated multiplex analysis virtual screening (IMA-VS), which comprises the evaluation of their (i) fitting physicochemical properties to the chemical environment of the target enzyme; (ii) active-site homing electrostatic potential to the target enzyme; (iii) structural fitting to the target active site through molecular docking; and (iv) overall absorption, distribution, metabolism, excretion and toxicity (ADMET) profile. After the virtual selection of potential anticoagulant hits, all molecules were synthesized and candidates were evaluated in vitro for their anticoagulant and hemolytic profile. The most promising candidate pointed out by IMA-VS was compound 1-(3',4'-dichlorophenyl)-4-(4,5-dihydro-1H-imidazol-2-yl)-3-methyl-1H-pyrazole that shown to display factor Xa (FXa)-specific inhibitory activity in vitro, acting as an uncompetitive inhibitor with an inhibition constant (Ki) = 61.16 ± 12.96 µM, in addition to the lowest hemolytic activity of the series. Further experiments revealed the antithrombotic activity of this compound in an in vivo model of arterial thrombosis induced by FeCl 3 .

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Drug repositioning by structure-based virtual screening

Cited by 202 publications

References 115 publications

Drug Discovery Inspired by Mother Nature: Seeking Natural Biochemotypes and the Natural Assembly Rules of the Biochemome

Drug Discovery Inspired by Mother Nature: Seeking Natural Biochemotypes and the Natural Assembly Rules of the Biochemome

Identification of Anti-Inflammatory and Anti-Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases

Pyrazolyl-Tetrazoles and Imidazolyl-Pyrazoles as Potential Anticoagulants and their Integrated Multiplex Analysis Virtual Screening

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