Quantitative Structure-Activity Relationships of Renin Inhibitors

Gupta, Satya P.

doi:10.2174/1389557033488051

Cited by 9 publications

(5 citation statements)

References 22 publications

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“…QSAR models, unlike the pharmacophore models, can be used to find the positive or negative effect of a particular feature of a drug molecule to its activity. QSAR methods have been used successfully on various drug targets such as carbonic anhydrase [252–253], thrombin [254–255] and renin [256]. Different machine learning techniques have also been used in constructing QSAR models [257–259].…”

Section: Reviewmentioning

confidence: 99%

Computational methods in drug discovery

Leelananda

Lindert

2016

Beilstein J. Org. Chem.

474

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.

474

309

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“…Inhibition of renin, which exclusively cleaves angiotensinogen and is not involved in alternative pathways, would surpass the above drawbacks and provide an advantageous way of therapy for the treatment of hypertension without side effects [6]. In the past decade, a considerable number of structurally different synthetic renin inhibitors of excellent (sub-nanomolar) potency and selectivity has been described [7,8]. To guide the drug-discovery process and to perform automated inhibitor screening, a continuous assay at picomolar sensitivity is needed.…”

Section: Introductionmentioning

confidence: 99%

Highly sensitive intramolecularly quenched fluorogenic substrates for renin based on the combination of L-2-amino-3-(7-methoxy-4-coumaryl)propionic acid with 2,4-dinitrophenyl groups at various positions

Paschalidou

Neumann

Gerhartz

et al. 2004

Biochemical Journal

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The development of renin inhibitors for the treatment of hypertension requires highly sensitive substrates to evaluate potency and to characterize the mechanism of tight-binding inhibitors. A series of intramolecularly quenched fluorogenic renin substrates, based on the N-terminal tetradecapeptide sequence of human angiotensinogen (hTDP), was synthesized using a solid-phase technique. Incorporation of the fluorescent amino acid L-Amp [L-2-amino-3-(7-methoxy-4-coumaryl)propionic acid] and the DNP (2,4-dinitrophenyl) group at various positions resulted in >90% quenching efficiency and strong product fluorescence. Shortening the hTDP sequence to an octapeptide from histidine in P5 to histidine in P3' (substrate 3) resulted in an acceptable k(cat)/K(m) (41000 M(-1).s(-1)) and further systematic variation gave substrate 9, DNP-Lys-His-Pro-Phe-His-Leu-Val-Ile-His-L-Amp, with a k(cat)/K(m) value of 350000 M(-1).s(-1) and 94% quenching efficiency. The free side chain of lysine, replacing the isoleucine residue at P6 position in the angiotensinogen sequence, contributed to the increased value for k(cat). The pH dependence of k(cat)/K(m) for renin and substrate 9 showed that the optimal pH is at pH 6-7. It also showed two titrating groups on the acidic side of the pH optimum, and one titrating group with a pK(a) of 7.8 on the alkaline side. The combination of good kinetic and spectroscopic properties resulted in a >20-fold improvement in the sensitivity of renin assay, compared with the commercial substrate Arg-Glu(EDANS)-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-Lys(DABCYL)-Arg [where EDANS is 5-[(2-aminoethyl)amino]naphthalene-1-sulphonic acid and DABCYL is 4-(4-dimethylaminophenylazo)benzoic acid] (k(cat)/K(m)=268000 M(-1) x s(-1), quenching efficiency <80%). The detection limit in a microplate renin assay was 60 pM, making substrate 9 well suited for the evaluation of inhibitors at picomolar concentrations.

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“…Examples for the successful application of structure-based VS include the in silico identification of epidermal growth factor receptor inhibitors with anti-proliferative activity against cancer cells [41], the search for small-molecule inhibitors of the SARS virus [42], and the discovery of human xylulose reductase inhibitors for the treatment of complications from diabetes [43]. Ligand-based VS methodologies have been instrumental in the discovery of carbonic anhydrase [44] and renin inhibitors [45] as well as in the search for inhibitors of the vascular endothelial growth factor receptor kinase [45]. …”

Section: Introductionmentioning

confidence: 99%

Discovery of novel SERCA inhibitors by virtual screening of a large compound library

Elam

Lape

Deye

et al. 2011

European Journal of Medicinal Chemistry

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Two screening protocols based on recursive partitioning and computational ligand docking methodologies, respectively, were employed for virtual screens of a compound library with 345,000 entries for novel inhibitors of the enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA), a potential target for cancer chemotherapy. A total of 72 compounds that were predicted to be potential inhibitors of SERCA were tested in bioassays and 17 displayed inhibitory potencies at concentrations below 100 µM. The majority of these inhibitors were composed of two phenyl rings tethered to each other by a short link of one to three atoms. Putative interactions between SERCA and the inhibitors were identified by inspection of docking-predicted poses and some of the structural features required for effective SERCA inhibition were determined by analysis of the classification pattern employed by the recursive partitioning models.

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Quantitative Structure-Activity Relationships of Renin Inhibitors

Cited by 9 publications

References 22 publications

Computational methods in drug discovery

Computational methods in drug discovery

Highly sensitive intramolecularly quenched fluorogenic substrates for renin based on the combination of L-2-amino-3-(7-methoxy-4-coumaryl)propionic acid with 2,4-dinitrophenyl groups at various positions

Discovery of novel SERCA inhibitors by virtual screening of a large compound library

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