2D- and 3D-QSAR studies of a series of benzopyranes and benzopyrano[3,4b][1,4]-oxazines as inhibitors of the multidrug transporter P-glycoprotein

Jabeen, Ishrat; Wetwitayaklung, Penpun; Chiba, Peter; Pastor, Manuel; Ecker, Gerhard F.

doi:10.1007/s10822-013-9635-9

Cited by 17 publications

(10 citation statements)

References 37 publications

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“…Jabeen et al designed a series of QSAR studies on benzopyrane and benzopyrano[3,4 β ][1,4]‐oxazine scaffolds and, from several 2D descriptors, a partial least square regression was performed to determine the relationship with biological activity. In addition, 3D molecular conformations were also used to calculate molecular interaction fields for further usage in a QSAR model based on GRID‐independent descriptors through Consistent Large Auto and Cross Correlation algorithm.…”

Section: Sar Computational Modelsmentioning

confidence: 99%

“…A distance of 13.2–13.6 Å between the aromatic ring of the benzopyrane ring and a bulky group (with a large hydrophobic surface area) in a specific position was referred, along with a presence of two HBA separated by a distance ranging from approximately 8.8 to 9.2 Å. Additionally, it was also described that the most potent inhibitors, besides the extended conformation, have a HBD group or a hydrophobic feature far from heavily rigid‐shaped regions (12.8–13.2 Å and 15.2–15.6 Å, respectively). Therefore, for the benzopyrane analogs, activity was proved to be correlated with a large distance between a HBD/HYD feature and a particular steric hot spot …”

Section: Sar Computational Modelsmentioning

confidence: 99%

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Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

Ferreira

Santos

2014

WIREs Comput Mol Sci

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One of the greatest threats to cancer treatment is the development, by some tumors, of resistance to the pharmacological action of several structurally unrelated cytotoxic agents-multidrug resistance (MDR). As P-glycoprotein (P-gp) is one of the most studied ATP-dependent efflux pumps that are frequently involved in drug efflux from cancer cells, the development of MDR modulators with the ability to inhibit P-gp efflux is considered a promising approach for overcoming MDR. However, the development of P-gp modulators have been hampered due to the absence of knowledge on the intrinsic molecular aspects by which efflux occurs, namely the specific steps that correlates drug recognition, ATP binding and efflux-related conformational changes. Experimental evidences for these processes are also difficult to obtain and only provide small pieces of information that need to be assembled for better comprehension of a wider and complex process that is drug efflux. A promising alternative relies on cutting-edge computational techniques to provide new insights on key aspects that are determinant to understand how P-gp efflux can be effectively reversed. With the contribution of ligand-based or structure-based computational methods, P-gp drug efflux is slowly becoming a dynamic and reactive process rather than a simple response to drug binding, with the complex architecture of ABC transporters playing a determinant role not only in drug recognition but in the coordination of ATP-driven conformational changes that ultimately drives drug efflux. The major enlightenments that computational studies provided toward a better comprehension of MDR and P-gp efflux phenomena are hereby described.The demographic effect of this pathology on the general population, especially in the industrialized countries, is becoming severely affected by a rapid increase in the number of new cancers (Figure 1). It is estimated that by 2030 the number of new cases (excluding nonmelanoma skin cancer) will grow 32.8% (more than 21 million), with an estimated increase of 34.6% (1.3 million) in the total number of deaths. 2,3 Thus, new and improved chemotherapy regimens are needed to counterweight such predictions. However, cancer therapy evolution is directly related to a greater knowledge on the basic molecular mechanisms Volume 5, January/February 2015 Although the above structures contributed to a better comprehension of the ABC exporters' topology, a Volume 5, January/February 2015

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Section: Sar Computational Modelsmentioning

confidence: 99%

Section: Sar Computational Modelsmentioning

confidence: 99%

Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

Ferreira

Santos

2014

WIREs Comput Mol Sci

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“…Optimal distances between hydrophobic, hydrogen bond donor and acceptor groups are also described to be important for efflux modulation as these moieties increase the probability of establishing p-p, CH-p or hydrogen bonds with residues inside the drug-binding pocket. 23 Nonetheless, optimal log P values are always required to allow higher partition rates towards the lipid bilayer. 24 The above studies were specifically designed to better understand the interaction between molecules and hypothetical drug-binding sites located at the transmembrane domains inside the lipid bilayer.…”

Section: Introductionmentioning

confidence: 99%

Do adsorbed drugs onto P-glycoprotein influence its efflux capability?

Ferreira

Santos

2015

Phys. Chem. Chem. Phys.

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The membrane biophysical aspects by which multidrug resistance (MDR) relate to the ABC transporter function still remain largely unknown. Notwithstanding the central role that efflux pumps like P-glycoprotein have in MDR onset, experimental studies classified additionally the lipid micro-environment where P-gp is inserted as a determinant for the increased efflux capability demonstrated in MDR cell lines. Recently, a nonlinear model for drug-membrane interactions showed that, upon drug adsorption, long-range mechanical alterations are predicted to affect the P-gp ATPase function at external drug concentrations of ∼10-100 μM. However, our results also show that drug adsorption may also occur at P-gp nucleotide-binding domains where conformational changes drive the efflux cycle. Thus, we assessed the effect of drug adsorption to both protein-water and lipid-water interfaces by means of molecular dynamics simulations. The results show that free energies of adsorption are lower for modulators in both lipid/water and protein/water interfaces. Important differences in drug-protein interactions, protein dynamics and membrane biophysical characteristics were observed between the different classes. Therefore, we hypothesize that drug adsorption to the protein and lipid-water interface accounts for a complex network of events that affect the ability of transporters to efflux drugs.

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“…Alignment-independent methods like GRIND overcome the problem with alignment and this method is widely used in SAR research. [26][27][28][29] Important positions around molecules (hot spots) are extracted from MIFs using AMANDA discretization algorithm. [30] Encoding of the filtered MIFs into GRIND variables was performed by the maximal auto-and cross-correlation (MACC2) algorithm.…”

Section: Molecular Similaritymentioning

confidence: 99%

Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strains

Cvijetić

Verbić

Resende

et al. 2018

European Journal of Medicinal Chemistry

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Antimicrobial resistance (AMR) is a major health problem worldwide, because of ability of bacteria, fungi and viruses to evade known therapeutic agents used in treatment of infections. Aryldiketo acids (ADK) have shown antimicrobial activity against several resistant strains including Gram-positive Staphylococcus aureus bacteria. Our previous studies revealed that ADK analogues having bulky alkyl group in ortho position on a phenyl ring have up to ten times better activity than norfloxacin against the same strains. Rational modifications of analogues by introduction of hydrophobic substituents on the aromatic ring has led to more than tenfold increase in antibacterial activity against multidrug resistant Gram positive strains. To elucidate a potential mechanism of action for this potentially novel class of antimicrobials, several bacterial enzymes were identified as putative targets according to literature data and pharmacophoric similarity searches for potent ADK analogues. Among the seven bacterial targets chosen, the strongest favorable binding interactions were observed between most active analogue and S. aureus dehydrosqualene synthase and DNA gyrase. Furthermore, the docking results in combination with literature data suggest that these novel molecules could also target several other bacterial enzymes, including prenyl-transferases and methionine aminopeptidase. These results and our statistically significant 3D QSAR model could be used to guide the further design of more potent derivatives as well as in virtual screening for novel antibacterial agents.

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2D- and 3D-QSAR studies of a series of benzopyranes and benzopyrano[3,4b][1,4]-oxazines as inhibitors of the multidrug transporter P-glycoprotein

Cited by 17 publications

References 37 publications

Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

Do adsorbed drugs onto P-glycoprotein influence its efflux capability?

Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strains

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