Molecular shape and electrostatics in the encoding of relevant chemical information

Nicholls, Anthony; Grant, Jennifer

doi:10.1007/s10822-005-9019-x

Cited by 39 publications

(35 citation statements)

References 27 publications

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“…where O ij = the pairwise combo score value between conformations i and j as aligned by ROCS [9][10][11] and N is the total number of conformations. After the matrix has been constructed the overlap average for each row of the matrix is computed by the formula Fig.…”

Section: Query Preparation Using Coralmentioning

confidence: 99%

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Computation of 3D queries for ROCS based virtual screens

Tawa

Baber²,

Humblet

2009

J Comput Aided Mol Des

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Rapid overlay of chemical structures (ROCS) is a method that aligns molecules based on shape and/or chemical similarity. It is often used in 3D ligand-based virtual screening. Given a query consisting of a single conformation of an active molecule ROCS can generate highly enriched hit lists. Typically the chosen query conformation is a minimum energy structure. Can better enrichment be obtained using conformations other than the minimum energy structure? To answer this question a methodology has been developed called CORAL (COnformational analysis, Rocs ALignment). For a given set of molecule conformations it computes optimized conformations for ROCS screening. It does so by clustering all conformations of a chosen molecule set using pairwise ROCS combo scores. The best representative conformation is that which has the highest average overlap with the rest of the conformations in the cluster. It is these best representative conformations that are then used for virtual screening. CORAL was tested by performing virtual screening experiments with the 40 DUD (Directory of Useful Decoys) data sets. Both CORAL and minimum energy queries were used. The recognition capability of each query was quantified as the area under the ROC curve (AUC). Results show that the CORAL AUC values are on average larger than the minimum energy AUC values. This demonstrates that one can indeed obtain better ROCS enrichments with conformations other than the minimum energy structure. As a result, CORAL analysis can be a valuable first step in virtual screening workflows using ROCS.

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Section: Query Preparation Using Coralmentioning

confidence: 99%

“…One tool that is extensively used is ROCS (Rapid overlay of chemical structures) [9][10][11]. ROCS is a 3D method that aligns compounds based on shape and/or chemical similarity.…”

Section: Introductionmentioning

confidence: 99%

Computation of 3D queries for ROCS based virtual screens

Tawa

Baber²,

Humblet

2009

J Comput Aided Mol Des

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“…Ideally the bound conformation of the query is known, but one can also use a single or multiple lowenergy conformations of the lead [6].…”

Section: Discussionmentioning

confidence: 99%

Computational Chemistry in Early-Stage Drug Discovery

Brooijmans¹

2008

AACR Education book

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“…The degree of structural similarity was calculated using ComboScore, the sum of the Shape Tanimoto and the Scaled Color values. 33 EON 34,35 is an electrostatics comparison program, it compares electrostatic potential maps of pre-aligned molecules and determines the Tanimoto measures for the comparison. The similarity between the compounds and GTP-α-S was also accessed in terms of electrostatic potential with the program EON.…”

Section: Methodsmentioning

confidence: 99%

“…The combination of ROCS and EON potentially yields compounds with similar shape and electrostatics. 34,35 Target based virtual screening methods FRED (Fast Exhaustive Docking, version 2.2.5), was used for docking purposes. The 3D structure of diguanylate cyclase PLED (PDB ID 2V0N) used for docking was prepared with the MAKE RECEPTOR program.…”

Section: Eonmentioning

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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Molecular shape and electrostatics in the encoding of relevant chemical information

Cited by 39 publications

References 27 publications

Computation of 3D queries for ROCS based virtual screens

Computation of 3D queries for ROCS based virtual screens

Computational Chemistry in Early-Stage Drug Discovery

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

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