scholarly journals Activity Landscape and Molecular Modeling to Explore the SAR of Dual Epigenetic Inhibitors: A Focus on G9a and DNMT1

2018 ◽  
Author(s):  
Edgar López-López ◽  
Fernando D. Prieto-Martínez ◽  
José L. Medina-Franco
Keyword(s):  
Data Set ◽  
Structure Activity ◽  
Activity Difference ◽  
Dual Inhibitors ◽  
Structure Similarity ◽  
Dynamics Simulations ◽  
Key Residues ◽  
High Structure ◽  
Molecular Docking And Dynamics ◽  
Activity Cliffs

In this work we discuss the insights from activity landscape, docking and molecular dynamics towards the understanding of the structure-activity relationships of dual inhibitors of major epigenetic targets: lysine metiltransferase (G9a) and DNA metiltranferase 1 (DNMT1). The study was based on a novel data set of 50 published compounds with reported experimental activity for both targets. The activity landscape analysis revealed the presence of activity cliffs, e.g., pairs of compounds with high structure similarity but large activity difference. Activity cliffs were further rationalized at the molecular level by means of molecular docking and dynamics simulations that led to the identification of interactions with key residues involved in the dual activity or selectivity with the epigenetic targets.

scholarly journals Activity Landscape and Molecular Modeling to Explore the SAR of Dual Epigenetic Inhibitors: A Focus on G9a and DNMT1

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3282 ◽  
Author(s):  
Edgar López-López ◽  
Fernando Prieto-Martínez ◽  
José Medina-Franco
Keyword(s):  
Data Set ◽  
Structure Activity ◽  
Lysine Methyltransferase ◽  
Dual Inhibitors ◽  
Structure Similarity ◽  
Dynamics Simulations ◽  
Key Residues ◽  
High Structure ◽  
Molecular Docking And Dynamics ◽  
Activity Cliffs

In this work we discuss the insights from activity landscape, docking and molecular dynamics towards the understanding of the structure-activity relationships of dual inhibitors of major epigenetic targets: lysine methyltransferase (G9a) and DNA methyltranferase 1 (DNMT1). The study was based on a novel data set of 50 published compounds with reported experimental activity for both targets. The activity landscape analysis revealed the presence of activity cliffs, e.g., pairs of compounds with high structure similarity but large activity differences. Activity cliffs were further rationalized at the molecular level by means of molecular docking and dynamics simulations that led to the identification of interactions with key residues involved in the dual activity or selectivity with the epigenetic targets.

Multi-Targeting Anticancer Agents: Rational Approaches, Synthetic Routes and Structure Activity Relationship

2019 ◽  
Vol 19 (7) ◽  
pp. 842-874 ◽  
Author(s):  
Harbinder Singh ◽  
Nihar Kinarivala ◽  
Sahil Sharma
Keyword(s):  
Anticancer Agents ◽  
Cancer Drug ◽  
Design And Synthesis ◽  
Cancer Drug Discovery ◽  
Dual Targeting ◽  
Structure Activity ◽  
Anti Cancer ◽  
Dual Inhibitors ◽  
Recent Trends ◽  
Synthetic Routes

We live in a world with complex diseases such as cancer which cannot be cured with one-compound one-target based therapeutic paradigm. This could be due to the involvement of multiple pathogenic mechanisms. One-compound-various-targets stratagem has become a prevailing research topic in anti-cancer drug discovery. The simultaneous interruption of two or more targets has improved the therapeutic efficacy as compared to the specific targeted based therapy. In this review, six types of dual targeting agents along with some interesting strategies used for their design and synthesis are discussed. Their pharmacology with various types of the molecular interactions within their specific targets has also been described. This assemblage will reveal the recent trends and insights in front of the scientific community working in dual inhibitors and help them in designing the next generation of multi-targeted anti-cancer agents.

scholarly journals Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jerónimo Laiolo ◽  
Priscila Ailin Lanza ◽  
Oscar Parravicini ◽  
Cecilia Barbieri ◽  
Daniel Insuasty ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Molecular Complexes ◽  
Binding Mode ◽  
Reversal Agents ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Doxorubicin Toxicity ◽  
Key Residues ◽  
Nanomolar Range ◽  
Experimental Structure

AbstractP-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure–activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone to the moiety bearing the pyrimidine favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4–7 and 12 is required for inhibition.

Quinolin-2-one-pyrimidine Hybrids Acting as Potent Reversal Agents on the P-gp-mediated Multidrug Resistance: Insights into Structure-activity Relationships and the Binding Mode

2021 ◽  
Author(s):  
Jerónimo Laiolo ◽  
Priscila Ailin Lanza ◽  
Oscar Parravicini ◽  
Cecilia Barbieri ◽  
Daniel Insuasty ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Molecular Complexes ◽  
Binding Mode ◽  
Reversal Agents ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Doxorubicin Toxicity ◽  
Key Residues ◽  
Nanomolar Range ◽  
Experimental Structure

Abstract P-gp-associated multidrug resistance (MDR) is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure-activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone moiety favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4–7 and 12 is required for inhibition.

scholarly journals Peptides presenting the binding site of human CD4 for the HIV-1 envelope glycoprotein gp120

2012 ◽  
Vol 8 ◽  
pp. 1858-1866 ◽  
Author(s):  
Julia Meier ◽  
Kristin Kassler ◽  
Heinrich Sticht ◽  
Jutta Eichler
Keyword(s):  
Amino Acids ◽  
Binding Site ◽  
Envelope Glycoprotein ◽  
Conformational Stability ◽  
Cellular Receptor ◽  
Binding Assays ◽  
Glycoprotein Gp120 ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Hiv 1

Based on the structure of the HIV-1 glycoprotein gp120 in complex with its cellular receptor CD4, we have designed and synthesized peptides that mimic the binding site of CD4 for gp120. The ability of these peptides to bind to gp120 can be strongly enhanced by increasing their conformational stability through cyclization, as evidenced by binding assays, as well as through molecular-dynamics simulations of peptide–gp120 complexes. The specificity of the peptide–gp120 interaction was demonstrated by using peptide variants, in which key residues for the interaction with gp120 were replaced by alanine or D-amino acids.

scholarly journals Ion-water coupling controls class A GPCR signal transduction pathways

2020 ◽  
Author(s):  
Neil J. Thomson ◽  
Owen N. Vickery ◽  
Callum M. Ives ◽  
Ulrich Zachariae
Keyword(s):  
Binding Site ◽  
G Protein ◽  
Signal Transmission ◽  
Water Molecules ◽  
Long Distance ◽  
Protein Binding Region ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Extracellular Sodium ◽  
Communication Pathway

G-protein-coupled receptors (GPCRs) transmit signals across the cell membrane, forming the largest family of membrane proteins in humans. Most GPCRs activate through an evolutionarily conserved mechanism, which involves reorientation of helices and key residues, rearrangement of a hydrogen bonding network mediated by water molecules, and the expulsion of a sodium ion from a protonatable binding site. However, how these components interplay to engage the signal effector binding site remains elusive. Here, we applied information theory to molecular dynamics simulations of pharmaceutically important GPCRs to trace concerted conformational variations across the receptors. We discovered a conserved communication pathway that includes protein residues and cofactors and enables the exchange of information between the extracellular sodium binding site and the intracellular G-protein binding region, coupling the most highly conserved protonatable residues at long distance. Reorientation of internal water molecules was found to be essential for signal transmission along this pathway. By inhibiting protonation, sodium decoupled this connectivity, identifying the ion as a master switch that determines the receptors’ ability to move towards active conformations.

Molecular docking and dynamics simulations of novel drug targets

2021 ◽  
pp. 79-131
Author(s):  
Jangampalli Adi Pradeepkiran ◽  
Manne Munikumar ◽  
Kanipakam Hema ◽  
Pradeep Natarajan ◽  
S.B. Sainath
Keyword(s):  
Molecular Docking ◽  
Drug Targets ◽  
Dynamics Simulations ◽  
Novel Drug ◽  
Molecular Docking And Dynamics ◽  
Novel Drug Targets

SAR Modelling of Complex Phenomena: Probing Methodological Limitations

2003 ◽  
Vol 31 (4) ◽  
pp. 393-399
Author(s):  
Herbert S. Rosenkranz
Keyword(s):  
Contact Dermatitis ◽  
Allergic Contact Dermatitis ◽  
Systemic Toxicity ◽  
Activity Relationship ◽  
Data Sets ◽  
Data Set ◽  
Structure Activity ◽  
Model Complex ◽  
Complex Phenomena ◽  
Allergic Contact

The increased acceptance of the use of structure–activity relationship (SAR) approaches to toxicity modelling has necessitated an evaluation of the limitations of the methodology. In this study, the limit of the capacity of the MULTICASE SAR program to model complex biological and toxicological phenomena was assessed. It was estimated that, provided the data set consists of at least 300 chemicals, divided equally between active and inactive compounds, the program is capable of handling phenomena that are even more “complex” than those modelled up to now (for example, allergic contact dermatitis, Salmonella mutagenicity, biodegradability, inhibition of tubulin polymerisation). However, within the data sets currently used to generate SAR models, there are limits to the complexity that can be handled. This may be the situation with regard to the modelling of systemic toxicity (for example, the LD50).

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