MONA – Interactive manipulation of molecule collections

Hilbig, Matthias; Urbaczek, Sascha; Groth, Inken; Heuser, Stefan; Rarey, Matthias

doi:10.1186/1758-2946-5-38

Cited by 28 publications

(41 citation statements)

References 13 publications

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“…Due to time constraints, the SAR interactions of the molecules which were generated via ViCi ® Hamburg [9] and LigBuilder ® v1.2 [8] were not studied in depth with the use of other software. This could have been beneficial as more molecular possibilities could have been identified which could have optimised binding with the P-glycoprotein site even further.…”

Section: Resultsmentioning

confidence: 99%

“…The P-gp LBP as circumscribed by the selected optimal conformers of Verapamil was analysed in LigBuilder v1.2 [8], thus enabling elucidation of the 3D volume available for novel molecule design, and of a general pharmacophoric structure, designated according to polarity, that all de novo designed ligands would necessarily need to conform to. The designed seed structures were allowed user directed molecular growth at pre-designated H.spc hydrogen atoms using the LINK algorithm of LigBuilder v1.2 [8].…”

Section: Methods 1: De Novo Drug Design Approachmentioning

confidence: 99%

“…The designed seed structures were allowed user directed molecular growth at pre-designated H.spc hydrogen atoms using the LINK algorithm of LigBuilder v1.2 [8].…”

Section: Methods 1: De Novo Drug Design Approachmentioning

confidence: 99%

See 2 more Smart Citations

Design and Optimisation of Novel Efflux Pump Inhibitors Using P-Glycoprotein as a Target

Bondin¹,

Shoemake²

2017

Drug Des

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This project utilised Verapamil as a lead molecule for iterative design of novel anti-cancer drugs with the potential to inhibit P-Glycoprotein (P-gp), a target which is overexpressed in malignant cells. The protein data bank crystallographic deposition 4M2S, describing the bound co-ordinates of P-gp bound to the small antagonist molecule QZ59-RRR, was used as a template for this study. Two drug design approaches were employed-de novo design and virtual screening (VS). For the former, the SYBYL

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Section: Resultsmentioning

confidence: 99%

Section: Methods 1: De Novo Drug Design Approachmentioning

confidence: 99%

See 1 more Smart Citation

Design and Optimisation of Novel Efflux Pump Inhibitors Using P-Glycoprotein as a Target

Bondin¹,

Shoemake²

2017

Drug Des

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“…A set-up file for each protomol was created; this contained the necessary information to guide small molecule docking to the protomol. The filtered molecular cohorts emanating from MONA® [23] when the best doi:10.11131/2017/101311 Page 6…”

Section: Virtual Screeningmentioning

confidence: 99%

“…MONA®, [23], a cheminformatics platform which facilitates compound library processing was used in order to filter the two molecular cohorts obtained from the molecular database ViCi® [22] for Lipinski Rule compliance.…”

Section: Virtual Screeningmentioning

confidence: 99%

Design of Novel Compounds with the Potential of Dual PPARγ/α Modulation for the Management of Metabolic Syndrome

Ellul¹,

Shoemake²

2017

Nuclear Receptor Research

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Abstract. This study sought to identify a single molecule capable of managing all three manifestations of metabolic syndrome-hyperglycaemia, dyslipidaemia and hypertension. Two Protein Data Bank (PDB) depositions were selected and used to establish the baseline affinity that any designed molecule in this study should ideally exceed in order to be considered for further optimisation. These were PDB depositions 3VN2 and 2P54 describing the bound co-ordinates of the Peroxisome Proliferator Activated Receptor (PPAR) partial agonist and Angiotensin II Receptor (Ang(II)R) blocker telmisartan and of the experimental PPAR fibrate agonist GW590735 bound to their respective cognate receptors. These small molecules were extracted from their cognate receptors, docked into their non-cognate counterparts, conformational analysis performed, and the optimal conformers were selected as template scaffolds in two parallel processes. The first was a fragment based de novo approach. Here, molecular moieties from the optimal telmisartan and GW590735 scaffolds modelled in their non-cognate targets and considered critical to binding were identified and modelled, in order to produce seed structures capable of sustaining molecular growth at user-directed sites designated as H.spc atoms subsequent to their being docked within the non-cognate Ligand Binding Pockets (LBPs). The second approach was a Virtual Screening (VS) exercise. Here, the optimal telmisartan and GW590735 conformers were submitted as query molecules to VS databases both individually and in the form of a consensus pharmacophore. This VS exercise identified structurally diverse molecules which were electronically and spatially similar to the queries and which were capable of modulating the target receptors. The molecular cohorts identified through both VS and the de novo approaches were filtered for Lipinski Rule compliance. The molecules that survived filtering were then re-docked into the non-cognate PPAR and/or _LBPs, conformational analysis re-performed and the affinity of the optimal conformer measured for its cognate receptor quantified. Comparison was made to the baseline and non-cognate receptor affinities previously established, and the molecules exhibiting dual affinities exceeding baseline values were selected for further optimisation. The use of the "tried and tested" Ang(II)R blocker and fibrate scaffolds as templates predisposes to the identification of novel structures devoid of unacceptable toxicity.

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Isolates from Alpinia officinarum Hance attenuate LPS‐induced inflammation in HepG2: Evidence from in silico and in vitro studies

Elgazar

Selim

Abdel-Hamid

et al. 2018

Phytotherapy Research

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In an attempt to connect the legacy of centuries of invaluable knowledge from traditional medicine and the current understanding to the molecular mechanism of diseases, we took the advantage of the emergence of in silico screening as a promising tool for identification of potential leads from libraries of natural products. Traditional Chinese Medicine database was subjected to structure based virtual screening for identification of anti-inflammatory compounds using the 3D crystal structure of p38 alpha mitogen activated protein kinase. The molecular docking studies revealed the potential activity of several classes of compounds known to be the constituents of the rhizomes of Alpinia officinarum Hance (Lesser galangal). Five compounds, galangin, kaempferide, isorhamnetin, and two diarylheptanoids, were isolated from the rhizomes of the plant using vacuum liquid chromatography and flash chromatography techniques. The anti-inflammatory activity of these compounds was investigated on HepG2 cells stimulated by lipopolysaccharide. The latter induced the gene expression of proinflammatory cytokines; interleukin-1β, interleukin-6, tumor necrosis factor alpha. Addition of the 5 isolated compounds downregulated this increased gene expression in a dose dependent manner. Thus, these results indicate that the isolated compounds from A. officinarum could be used as a beneficial source for preventing and treating inflammatory diseases.

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MONA – Interactive manipulation of molecule collections

Cited by 28 publications

References 13 publications

Design and Optimisation of Novel Efflux Pump Inhibitors Using P-Glycoprotein as a Target

Design and Optimisation of Novel Efflux Pump Inhibitors Using P-Glycoprotein as a Target

Design of Novel Compounds with the Potential of Dual PPARγ/α Modulation for the Management of Metabolic Syndrome

Isolates from Alpinia officinarum Hance attenuate LPS‐induced inflammation in HepG2: Evidence from in silico and in vitro studies

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