Structural and chemical basis for enhanced affinity and potency for a large series of estrogen receptor ligands: 2D and 3D QSAR studies

Salum, Lívia de Barros; Polikarpov, Igor; Andricopulo, Adriano D.

doi:10.1016/j.jmgm.2007.02.001

Cited by 44 publications

(51 citation statements)

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“…In addition, these results are highly compatible with the 3D environment of the ER binding site as demonstrated in Fig. 4c [21]. It is important to note that the degree to which a small molecule ligand binds to the ER active site is determined by multiple and complementary supramolecular interactions, which can be studied using specialized 2D molecular fragments, as well as a combination of molecular modeling and 2D and 3D QSAR studies.…”

Section: Hqsar: a Versatile Tool In Drug Designsupporting

confidence: 81%

“…Several HQSAR models for a variety of standard data sets consisting of ligands of important molecular targets have been generated throughout recent years [20,21,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], including cases where the 3D structure of the target protein was not yet available or the molecular target was unknown. It is important to note that besides predicting accurately property values of untested compounds (e.g., potency, affinity), HQSAR models can also provide useful insights into the relationships between structural fragments (micromolecule) and biological activity [25].…”

Section: Hqsar: a Versatile Tool In Drug Designmentioning

confidence: 99%

“…As an illustrative example of the integration of QSAR strategies, a study with a large series of flavanoids, dihydrobenzoxathiins and dihydrobenzodithiins as estrogen receptor (ER) modulators demonstrated that HQSAR and CoMFA (comparative molecular field analysis) studies can be carried out concomitantly to search for synergies between 2D and 3D QSAR technologies [21]. The HQSAR contribution map for the data set modulator having the highest binding affinity (IC 50 = 0.3 nM) for ER (Fig.…”

Section: Hqsar: a Versatile Tool In Drug Designmentioning

confidence: 99%

“…QSAR is a valuable drug design tool that applies statistical analysis of relationships between chemical structure and biological activity in a quantitative and mechanism-oriented manner [16][17][18][19]. QSAR technologies has been employed, and continue to be developed and employed, both to correlate information in data sets and to facilitate, for example, the discovery of enzyme inhibitors, agonist or antagonists of important drug targets [20][21][22][23][24]. As shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

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Fragment-based QSAR: perspectives in drug design

Salum

Andricopulo

2009

Mol Divers

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Drug design is a process driven by innovation and technological breakthroughs involving a combination of advanced experimental and computational methods. A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the optimization of leads into drug candidates. Quantitative structure-activity relationship (QSAR) methods are among the most important strategies that can be applied for the successful design of small molecule modulators having clinical utility. Hologram QSAR (HQSAR) is a modern 2D fragment-based QSAR method that employs specialized molecular fingerprints. HQSAR can be applied to large data sets of compounds, as well as traditional-size sets, being a versatile tool in drug design. The HQSAR approach has evolved from a classical use in the generation of standard QSAR models for data correlation and prediction into advanced drug design tools for virtual screening and pharmacokinetic property prediction. This paper provides a brief perspective on the evolution and current status of HQSAR, highlighting present challenges and new opportunities in drug design.

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Section: Hqsar: a Versatile Tool In Drug Designsupporting

confidence: 81%

Section: Hqsar: a Versatile Tool In Drug Designmentioning

confidence: 99%

Section: Hqsar: a Versatile Tool In Drug Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fragment-based QSAR: perspectives in drug design

Salum

Andricopulo

2009

Mol Divers

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“…17,18 Quantitative structure-activity relationship (QSAR) methods have been successfully employed to assist the design of new small molecule drug candidates, ranging from enzyme inhibitors to receptor ligands. [19][20][21][22][23][24][25][26] However, there is only a small number of QSAR studies found in the literature for taxoid-site tubulin modulators and, to the best of our knowledge, no 3D QSAR investigation of discodermolide analogs has been reported to date. 25,[27][28][29][30] This proves the importance of QSAR studies involving this class of tubulin modulators.…”

Section: -15mentioning

confidence: 99%

Structural and chemical basis for anticancer activity of a series of²-tubulin ligands: molecular modeling and 3D QSAR studies

Salum¹,

Dias²,

Andricopulo³

2009

J. Braz. Chem. Soc.

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Uma estratégia importante para a terapia do câncer é o planejamento de modulares que interferem na dinâmica dos microtúbulos através de sua ligação específica à subunidade β da tubulina. No presente trabalho, estudos de análise comparativa dos campos moleculares (CoMFA) foram realizados com uma série de análogos do discodermolídeo com ação antimitótica. Resultados significativos foram obtidos (CoMFA (i) , q 2 = 0,68, r 2 = 0,94; CoMFA (ii) , q 2 = 0,63, r 2 = 0,91), indicando a elevada consistência interna e externa dos modelos gerados empregando duas estratégias independentes de alinhamento estrutural. Os modelos foram validados externamente com um conjunto teste e os valores preditos apresentaram boa concordância com os resultados experimentais. Os modelos de QSAR e os mapas de contorno 3D forneceram importantes informações sobre as bases químicas e estruturais envolvidas no processo de reconhecimento molecular dessa família de análogos do discodermolídeo, sendo uma valiosa ferramenta no planejamento de novos moduladores específicos da β-tubulina com potente atividade antitumoral.An important approach to cancer therapy is the design of small molecule modulators that interfere with microtubule dynamics through their specific binding to the β-subunit of tubulin. In the present work, comparative molecular field analysis (CoMFA) studies were conducted on a series of discodermolide analogs with antimitotic properties. Significant correlation coefficients were obtained (CoMFA (i) , q 2 = 0.68, r 2 = 0.94; CoMFA (ii) , q 2 = 0.63, r 2 = 0.91), indicating the good internal and external consistency of the models generated using two independent structural alignment strategies. The models were externally validated employing a test set, and the predicted values were in good agreement with the experimental results. The final QSAR models and the 3D contour maps provided important insights into the chemical and structural basis involved in the molecular recognition process of this family of discodermolide analogs, and should be useful for the design of new specific β-tubulin modulators with potent anticancer activity.Keywords: cancer, drug design, discodermolide, microtubule, β-tubulin IntroductionA rational approach to cancer therapy involves the design of small molecule ligands that interfere with microtubule dynamics through their specific binding to the β-subunit of tubulin, leading to mitotic arrest and cell death.1-6 Taxol (paclitaxel, Figure 1), a highly functionalized diterpenoid isolated from Taxus brevifolia (Pacific Yew tree), was the first compound recognized to interact specifically and reversibly with the β-subunit of the tubulin heterodimer, promoting microtubule stabilization and consequently, blocking cells in the mitotic phase of the cell cycle. The unique mechanism of action as a microtubule-stabilizing antimitotic agent (MSAA) is responsible by the extraordinary clinical success achieved by Taxol and related taxanes in the treatment of a variety of cancers. Although taxanes are the most prominent amon...

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Recent Trends in Structure‐Based Drug Design and Energetics

Andricopulo

Güido

Trivella

et al. 2010

Burger's Medicinal Chemistry and Drug Discovery

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The integration of cheminformatics tools, thermodynamic data, and structural information play a major role in the drug discovery process. Altogether, these methods can describe the molecular forces that govern the affinity and selectivity of bioactive molecules for their macromolecular targets. By being able to uncover the relationships between structure and energetics when using high‐resolution structural information and modern biophysical methods, one can fulfill the challenge of correctly interpreting drug–macromolecular interactions. These interactions are prone to be unveiled and scrutinized when structure‐based drug design is applied to a known three‐dimensional (3D) structure of a given protein. If fully integrated with structure‐based ligand design in an iterative way, computational methods can be of invaluable help to describe the ligand–target (cocomplex) formation. Structure‐based virtual screening can be used to rapid cherry‐pick the best candidates from a large pool of compounds in a chemical library after docking into the active sites of 3D protein structures. To pursue this, the quantification of favorable and unfavorable interactions requires knowledge of the thermodynamics of the interactions. Docking algorithms and molecular dynamics simulations can be used to predict binding energies for positioning ligands in target binding sites, but they only provide information regarded to the prediction of the change in the Gibbs free energy change, which hampers the thoroughly dissection of all other very important thermodynamic parameters—enthalpy, entropy, and heat capacity change. The major goal of this chapter is to show the integration of structure‐based drug design with the energetic. Microcalorimetric measurement of the drug–macromolecular interaction is an effective way to enhance the power, the medicinal chemists have on hand, to pursue a knowledge‐based approach toward the description of all of the noncovalent bond terms that take place in the cocomplex formation.

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Structural and chemical basis for enhanced affinity and potency for a large series of estrogen receptor ligands: 2D and 3D QSAR studies

Cited by 44 publications

References 51 publications

Fragment-based QSAR: perspectives in drug design

Fragment-based QSAR: perspectives in drug design

Structural and chemical basis for anticancer activity of a series of²-tubulin ligands: molecular modeling and 3D QSAR studies

Recent Trends in Structure‐Based Drug Design and Energetics

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