Disease relevance of Drug Design

• This finding provides the possibility of new drug design strategies for autoimmunity and multiple myeloma focused on blocking Blimp-1 expression or activity [1].
• To aid in structure-based drug design studies against toxoplasmosis, the crystal structures of the T.gondii apo UPRTase (1.93 A resolution), the UPRTase bound to its substrate, uracil (2.2 A resolution), its product, UMP (2.5 A resolution), and the prodrug, 5-fluorouracil (2.3 A resolution), have been determined [2].
• The proteinase of the human immunodeficiency virus (HIV-1 protease) is an obvious example of a receptor for which drug design methodologies have been successfully applied [3].
• HIV protease (PR) represents a prime target for rational drug design, and protease inhibitors (PI) are powerful antiviral drugs [4].
• CONCLUSIONS: Adenosine-regulating agents that act in an event- and site-specific manner represent a novel drug design strategy that may potentially be valuable for the long-term treatment of supraventricular arrhythmias and control of ventricular rate during atrial fibrillation or flutter [5].

Psychiatry related information on Drug Design

• Memapsin 2 (beta-secretase) is a membrane-associated aspartic protease involved in the production of beta-amyloid peptide in Alzheimer's disease and is a major target for drug design [6].
• Using a combination of an alternating treatment and double-blind placebo-controlled drug design, the independent and combined effects of two behavioral interventions and two doses of methylphenidate (MPH) in 3 children with Attention Deficit Hyperactivity Disorder (ADHD) and mental retardation (MR) were assessed [7].

High impact information on Drug Design

• Because the Id genes are expressed at very low levels in adults, they make attractive new targets for anti-angiogenic drug design [8].
• Thus, benzodiazepine-induced behavioural responses are mediated by specific GABA(A) receptor subtypes in distinct neuronal circuits, which is of interest for drug design [9].
• Atomic structure of thymidylate synthase: target for rational drug design [10].
• This PPAR-gamma-dependent anti-inflammatory mechanism defines new cellular targets for therapeutic drug design and interventions for the treatment of chronic inflammation [11].
• The details of the structure lead to a model for the mechanism of UL42, provide the basis for drug design, and allow modeling of other proteins that lack sequence homology with UL42 or PCNA [12].

Chemical compound and disease context of Drug Design

• The potent inhibitory effect of diospyrin on type I DNA topoisomerase from L. donovani can be exploited for rational drug design in human leishmaniasis [13].
• Inhibition of AdoHcy hydrolase represents a new approach to human cytomegalovirus drug design that should be pursued [14].
• We have recently reported an influenza virus neuraminidase inhibitor, RWJ-270201 (BCX-1812), a novel cyclopentane derivative discovered through structure-based drug design [15].
• CONCLUSIONS: ¿Tomudex' represents the successful culmination of a rational drug design programme, and shows promise as a new cytotoxic for the treatment of colorectal cancer [16].
• As predicted, the order of fit into DNA correlated with the relative ability to inhibit estrogen-induced growth of tumor cells suggesting that the evolving drug design technology will be valuable in developing new drugs for breast cancer [17].

Biological context of Drug Design

• If the interplay between caspase proteases and mitochondria decide the fate of the cell during apoptosis, they may constitute useful molecular targets for novel drug design [18].
• Active site of trypanothione reductase. A target for rational drug design [19].
• These results are discussed in the context of a computer modeled structure of the ternary complexes of RT, DNA/RNA primer-template, and SddCTP analogues as well as implications for structure-activity relationships and further drug design [20].
• The enzyme trypanothione reductase (TR), together with its substrate, the glutathione-spermidine conjugate trypanothione, plays an essential role in protecting parasitic trypanosomatids against oxidative stress and is a target for drug design [21].
• Dimerization of G-protein-coupled receptors: implications for drug design and signaling [22].

Anatomical context of Drug Design

• The structure enables modelling of the docking interactions to its ligands, for example from focal adhesion kinase, and supports structure-based drug design of inhibitors of the CAS-FAK interaction [23].
• Abnormally high human neutrophil elastase (HNE) levels are involved in several diseases; therefore, inhibitors of HNE are of interest as targets for drug design [24].
• It is interesting to find that P8 and P9 peptides inhibited syncytia formation, suggesting that the P8 and P9 spanning regions may provide a good target for anti-SARS-CoV drug design [25].
• PNP is therefore a target for inhibitor development aiming at T-cell immune response modulation and has been submitted to extensive structure-based drug design [26].
• Previous reports from this laboratory have shown marked cytocidal effects of the ISIS-3466 antisense phosphorothioate oligodeoxynucleotide to the human nucleolar protein p120 on human cancer cell lines in vitro and inhibition of tumor growth in vivo in an i.p/i.p. LOX cell model (L. Perlaky et al. Anti-Cancer Drug Design 8:3-14, 1993) [27].

Associations of Drug Design with chemical compounds

• Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4, 6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors [28].
• Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design [29].
• Inhibitors combining guanidinium-like structural motifs with long chains specifically targeting this residue are good candidates for rational isoform-specific drug design [30].
• This trypanothione-dependent glyoxalase I is therefore an attractive focus for additional biochemical and genetic investigation as a possible target for rational drug design [31].
• The generation of eicosanoids (prostaglandins, leukotrienes, and lipoxins), oxygenated lipids, and PAF remain the focus of rational drug design targets given their established roles in cell-cell communication and as mediators in inflammation and pathophysiologic events [32].

Gene context of Drug Design

• The perforin/granzyme pathway may therefore represent a novel target for anti-GvHD drug design [33].
• The susceptibility differences to RR inhibitors between p53R2 and hRRM2 may lead to a new direction in drug design for human cancer treatment [34].
• Reconstitution of p16 function in transformed cells is therefore an attractive target for anti-cancer drug design [35].
• Altogether, we have identified a minimal peptide that inhibits Stat3 signaling and provides the conceptual basis for use of this peptide as a lead for novel peptidomimetic drug design [36].
• Based on this study, we propose a model for a complex with the RARgamma-specific agonist CD666 that shows the possible applications for structure-based drug design of RAR isotype-selective retinoids [37].

Analytical, diagnostic and therapeutic context of Drug Design

• The progress made in the crystallization of protein kinases has confirmed that the ATP-binding domain of tyrosine kinases is an attractive target for drug design [38].
• The cysteine proteases of two trypanosomes, Trypanosoma cruzi (cruzain) and Trypanosoma brucei (rhodesain), have been targeted for a structure-based drug design program as mechanistic inhibitors that target these enzymes are effective in cell-based and animal models of trypanosomal infection [39].
• Because of its critical role in purine biosynthesis, IMPDH is a drug design target for anticancer, antiinfective, and immunosuppressive chemotherapy [40].
• Surface plasmon resonance thermodynamic and kinetic analysis as a strategic tool in drug design. Distinct ways for phosphopeptides to plug into Src- and Grb2 SH2 domains [41].
• To understand the structural basis of this differential sensitivity and begin a structure-based drug-design cycle for PfDHODH inhibitors, the three-dimensional structure (2.4 Angstroms, R = 20.1%) of PfDHODH bound to the active metabolite of leflunomide was determined by X-ray crystallography [42].

References