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Overexpression of ABC transporters like P-glycoprotein (P-gp) has been correlated with resistances in cancer chemotherapy. Intensive efforts to identify P-gp inhibitors for use in combination therapy have not led to clinically approved inhibitors to date. Here we describe computational approaches combined with structure-based design to improve the characteristics of a P-gp inhibitor previously identified by us. This hit compound represents a novel class of P-gp inhibitors that specifically targets and inhibits P-gp ATP hydrolysis, while not being transported by the pump. We describe here a new program for virtual chemical synthesis and computational assessment, ChemGen, to produce hit compound variants with improved binding characteristics. The chemical syntheses of several variants, efficacy in reversing multidrug resistance in cell culture and biochemical assessment of the inhibition mechanism are described. The usefulness of the computational predictions of binding characteristics of the inhibitor variants is discussed and compared to more traditional structure based approaches.
This article was published in the following journal.
Name: Journal of medicinal chemistry
Acetylation, a key component in post-translational modification regulated by HATs and HDACs, is relevant to many crucial cellular contexts in organisms. Based on crucial pharmacophore patterns and the...
To assess cancer detection rates of different target-dependent transperineal magnetic resonance (MR) / ultrasound (US) fusion-guided biopsy templates with reduced number of systematic cores.
Epidermal growth factor receptor (EGFR) signaling pathway is one of the promising and well-established targets for anticancer therapy. The objective of the present study was to identify new EGFR inhib...
A structure-guided design strategy was used to improve the resistance profile of HIV-1 protease inhibitors by optimizing hydrogen bonding and van der Waals interactions with the protease while staying...
It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y inhibitors.
Aim of the study is to examine the effects of glycoprotein IIb/IIIa inhibitors on reperfusion success assessed by cardiac magnetic resonance imaging in patients with myocardial infarction ...
The hypothesis of the study is that targeted MRI/US fusion-guided prostate biopsy with additional systematic transrectal ultrasound (TRUS)-guided biopsy significantly detects more prostate...
Anti-platelet therapy is a key point of acute myocardial infarction (AMI) treatment. Nowadays, dual anti-platelet therapy based on aspirin and ADP-P2Y12 receptor inhibitor is the preferred...
Computational simulation will be performed to represent motion of knees with a dislocating kneecap. Common surgical treatment methods will be simulated and anatomical parameters commonly a...
To compare prostate cancer (PCa) detection rate of magnetic resonance (MR)-targeted biopsy and transrectal ultrasound (TRUS)-guided biopsy in patients with high PSA values and at least one...
A high affinity receptor for myelin-associated inhibitors (MAIs) that include NOGO-A PROTEIN; OLIGODENDROCYTE MYELIN GLYCOPROTEIN; and MYELIN-ASSOCIATED GLYCOPROTEIN. It is expressed primarily by neurons in the brain and OLFACTORY BULBS. During embryonic development, it is expressed in the PERIPHERAL NERVOUS SYSTEM. It localizes to GROWTH CONES and may inhibit neurite outgrowth following SPINAL INJURY.
Radiotherapy where cytotoxic radionuclides are linked to antibodies in order to deliver toxins directly to tumor targets. Therapy with targeted radiation rather than antibody-targeted toxins (IMMUNOTOXINS) has the advantage that adjacent tumor cells, which lack the appropriate antigenic determinants, can be destroyed by radiation cross-fire. Radioimmunotherapy is sometimes called targeted radiotherapy, but this latter term can also refer to radionuclides linked to non-immune molecules (see RADIOTHERAPY).
A 170-kDa transmembrane glycoprotein from the superfamily of ATP-BINDING CASSETTE TRANSPORTERS. It serves as an ATP-dependent efflux pump for a variety of chemicals, including many ANTINEOPLASTIC AGENTS. Overexpression of this glycoprotein is associated with multidrug resistance (see DRUG RESISTANCE, MULTIPLE).
An assessment of HEALTH STATUS requested by third parties (e.g. insurers, adjudicating bodies, law enforcement, attorneys, etc) on a subject’s functional ability. Such information may be used in optimizing treatment or making informed decisions on compensation.
Platelet membrane glycoprotein IIb is an integrin alpha subunit that heterodimerizes with INTEGRIN BETA3 to form PLATELET GLYCOPROTEIN GPIIB-IIIA COMPLEX. It is synthesized as a single polypeptide chain which is then postranslationally cleaved and processed into two disulfide-linked subunits of approximately 18 and 110 kDa in size.
Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer th...
Types of Cell Culture Open https://www.youtube.com/watch?v=WGKoJRNKADY to view video on cell culture basics. Four catagories of cell culture techniques are listed below: Adherent cells Cells shown to require attachment for growth are sa...