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Drug Design Strategies (drug + design_strategy)
Selected AbstractsNew developments in small molecules targeting p53 pathways in anticancer therapyDRUG DEVELOPMENT RESEARCH, Issue 6 2008Chit Fang Cheok Abstract The tumor suppressor p53 is frequently inactivated in a wide variety of cancers and point mutations or deletions of the p53 gene are associated with poor prognosis in cancer. About half of all human tumors carry wildtype p53 but p53 wildtype functions are often suppressed by the overexpression of murine double minute 2 (MDM2), a negative regulator of p53. Restoration of p53 functions in tumor cells, therefore, represents an attractive strategy in combating cancer and has been the focus of intensive anticancer drug discovery. One strategy is to antagonize MDM2 functions and initial success was demonstrated in vitro and in xenograft tumor models using newly discovered small molecule inhibitors and antisense oligonucleotides. The new discovery of a compound targeting SirT1 (a member of the sirtuin family) in a p53-dependent reporter screen highlighted the importance of another negative regulator of p53 and offers an additional avenue for drug discovery and research on p53-activating therapeutics. Here, we discuss the developments of p53-activating small molecules and their potential use in combination therapy with established chemotherapeutics. These small molecules were discovered from chemical library screening using biochemical assays or cellular-based assays, and/or structure-based rational drug design strategies. Drug Dev Res 69:289,296, 2008. © 2008 Wiley-Liss, Inc. [source] Interpretation of biological activity data of bacterial endotoxins by simple molecular models of mechanism of actionFEBS JOURNAL, Issue 3 2000Vladimir Frecer Lipid A moiety has been identified as the bioactive component of bacterial endotoxins (lipopolysaccharides). However, the molecular mechanism of biological activity of lipid A is still not fully understood. This paper contributes to understanding of the molecular mechanism of action of bacterial endotoxins by comparing molecular modelling results for two possible mechanisms with the underlying experimental data. Mechanisms of action involving specific binding of lipid A to a protein receptor as well as nonspecific intercalation into phospholipid membrane of a host cell were modelled and analysed. As the cellular receptor for endotoxin has not been identified, a model of a peptidic pseudoreceptor was proposed, based on molecular structure, symmetry of the lipid A moiety and the observed character of endotoxin-binding sites in proteins. We have studied the monomeric form of lipid A from Escherichia coli and its seven synthetic analogues with varying numbers of phosphate groups and correlated them with known biological activities determined by the Limulus assay. Gibbs free energies associated with the interaction of lipid A with the pseudoreceptor model and intercalation into phospholipid membrane calculated by molecular mechanics and molecular dynamics methods were used to compare the two possible mechanisms of action. The results suggest that specific binding of lipid A analogues to the peptidic pseudoreceptor carrying an amphipathic cationic binding pattern BHPHB (B, basic; H, hydrophobic; P, polar residue, respectively) is energetically more favourable than intercalation into the phospholipid membrane. In addition, binding affinities of lipid A analogues to the best minimum binding sequence KFSFK of the pseudoreceptor correlated with the experimental Limulus activity parameter. This correlation enabled us to rationalize the observed relationship between the number and position of the phosphate groups in the lipid A moiety and its biological activity in terms of specific ligand,receptor interactions. If lipid A,receptor interaction involves formation of phosphate-ammonium ion-pair(s) with cationic amino-acid residues, the specific mechanism of action was fully consistent with the underlying experimental data. As a consequence, recognition of lipid A variants by an amphipathic binding sequence BHPHB of a host-cell protein receptor might represent the initial and/or rate-determining molecular event of the mechanism of action of lipid A (or endotoxin). The insight into the molecular mechanism of action and the structure of the lipid A-binding pattern have potential implications for rational drug design strategies of endotoxin-neutralizing agents or binding factors. [source] Object-oriented approach to drug design enabled by NMR SOLVE: First real-time structural tool for characterizing protein,ligand interactionsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue S37 2001Daniel S. Sem Abstract As a result of genomics efforts, the number of protein drug targets is expected to increase by an order of magnitude. Functional genomics efforts are identifying these targets, while structural genomics efforts are determining structures for many of them. However, there is a significant gap in going from structural information for a protein target to a high affinity (Kd,<,100 nM) inhibitor, and the problem is multiplied by the sheer number of new targets now available. nature frequently designs proteins in classes that are related by the reuse, through gene duplication events, of cofactor binding domains. This reuse of functional domains is an efficient way to build related proteins in that it is object-oriented. There is a growing realization that the most efficient drug design strategies for attacking the mass of targets coming from genomics efforts will be systems-based approaches that attack groups of related proteins in parallel. We propose that the most effective drug design strategy will be one that parallels the object-oriented manner by which nature designed the gene families themselves. IOPE (Integrated Object-Oriented PharmacoEngineering) is such an approach. It is a three-step technology to build focused combinatorial libraries of potential inhibitors for major families and sub-families of enzymes, using cogent NMR data derived from representatives of these protein families. The NMR SOLVE (Structurally Oriented Library Valency Engineering) data used to design these libraries are gathered in days, and data can be obtained for large proteins (>,170 kDa). Furthermore, the process is fully object-oriented in that once a given bi-ligand is identified for a target, potency is retained if different cofactor mimics are swapped. This gives the drug design process maximum flexibility, allowing for the more facile transition from in vitro potency to in vivo efficacy. J. Cell. Biochem. Suppl. 37: 99,105, 2001. © 2002 Wiley-Liss, Inc. [source] Synthesis and calcium channel modulating effects of modified Hantzsch nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(pyridinyl or 2-trifluoromethylphenyl)-5-pyridinecarboxylatesDRUG DEVELOPMENT RESEARCH, Issue 4 2000Ramin Miri Abstract A group of racemic nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(pyridinyl or 2-trifluoromethylphenyl)-5-pyridinecarboxylates 8a,o were synthesized using modified Hantzsch reactions. In vitro calcium channel antagonist activities, determined using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay, showed that compounds 8a,o exhibited weaker calcium antagonist activity (10,5 to 10,7 M range) than the reference drug nifedipine (IC50 = 1.43 × 10,8 M). Compounds 8 possessing a C-4 R1 = 2-pyridyl substituent were always more potent than the approximately equiactive analogs having an R1 = 3-pyridyl, 4-pyridyl or 2-CF3 -C6H4 -substituent, within each subgroup of nitrooxyalkyl compounds [R2 = , (CH2)nONO2 (n = 2, 3, 4) or ,CH(CH2ONO2)2]. Although the length of the R2 = ,(CH2)nONO2 substituent (n = 2,4) was not a determinant of smooth muscle calcium antagonist activity when the C-4 R1 -substituent was 2-pyridyl, when R1 was a 3-pyridyl, 4-pyridyl, or 2-CF3 -C6H4 -substituent, the relative potency order with respect to the R2 = ,(CH2)nONO2 substituent was n = 3 and 4 > n = 2. Replacement of the isopropyl substituent of the ester moiety of the calcium antagonist (±)-2-pyridyl 3a by a ,(CH2)nONO2 (n = 2,4) moiety increased calcium antagonist activity on GPILSM by 8-fold. In contrast, replacement of the isopropyl substituent of the ester moiety of the calcium agonists (±)-3-pyridyl 3b, (±)-4-pyridyl 3c or the methyl substituent of the ester moiety of Bay K8644 by a R2 nitrooxyalkyl substituent resulted in abolition of their calcium agonist effects on GPILSM that is replaced by a smooth muscle calcium antagonist effect. These calcium antagonist data support the concept that incorporation of a nitrooxyalkyl ester substituent constitutes a valuable drug design strategy to enhance Hantzsch 1,4-dihydropyridine calcium antagonist and/or abolish calcium agonist effects on smooth muscle. Replacement of the isopropyl (8b,c), or the methyl (8d) group by a ,CH2CH2ONO2 moiety resulted in retention of the cardiac positive inotropic effect where the relative potency order with respect to the C-4 substituent was 2-CF3 -C6H6 - (8d) > 3-pyridyl (8b) , 4-pyridyl (8c). Model hybrid (calcium channel modulation, ·NO release) compounds, that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4-dihydropyridine CC modulator that offers a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure,function relationship of calcium channels. Drug Dev. Res. 51:225,232, 2000. © 2001 Wiley-Liss, Inc. [source] Object-oriented approach to drug design enabled by NMR SOLVE: First real-time structural tool for characterizing protein,ligand interactionsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue S37 2001Daniel S. Sem Abstract As a result of genomics efforts, the number of protein drug targets is expected to increase by an order of magnitude. Functional genomics efforts are identifying these targets, while structural genomics efforts are determining structures for many of them. However, there is a significant gap in going from structural information for a protein target to a high affinity (Kd,<,100 nM) inhibitor, and the problem is multiplied by the sheer number of new targets now available. nature frequently designs proteins in classes that are related by the reuse, through gene duplication events, of cofactor binding domains. This reuse of functional domains is an efficient way to build related proteins in that it is object-oriented. There is a growing realization that the most efficient drug design strategies for attacking the mass of targets coming from genomics efforts will be systems-based approaches that attack groups of related proteins in parallel. We propose that the most effective drug design strategy will be one that parallels the object-oriented manner by which nature designed the gene families themselves. IOPE (Integrated Object-Oriented PharmacoEngineering) is such an approach. It is a three-step technology to build focused combinatorial libraries of potential inhibitors for major families and sub-families of enzymes, using cogent NMR data derived from representatives of these protein families. The NMR SOLVE (Structurally Oriented Library Valency Engineering) data used to design these libraries are gathered in days, and data can be obtained for large proteins (>,170 kDa). Furthermore, the process is fully object-oriented in that once a given bi-ligand is identified for a target, potency is retained if different cofactor mimics are swapped. This gives the drug design process maximum flexibility, allowing for the more facile transition from in vitro potency to in vivo efficacy. J. Cell. Biochem. Suppl. 37: 99,105, 2001. © 2002 Wiley-Liss, Inc. [source] Structural and Biophysical Characterization of XIAP BIR3 G306E Mutant: Insights in Protein Dynamics and Application for Fragment-Based Drug DesignCHEMICAL BIOLOGY & DRUG DESIGN, Issue 3 2009Cathy D. Moore Previous reports describe modulators of X-linked inhibitor of apoptosis (XIAP),caspase interaction designed from the AVPI N-terminal peptide sequence of second mitochondria-derived activator of caspase. A fragment-based drug design strategy was initiated to identify therapeutic non-peptidomimetic antagonists of X-linked inhibitor of apoptosis protein,protein interactions. Fragments that bind to the AVPI binding site of BIR3 (bacculoviral inhibitory repeat) were identified, and to further localize the fragment binding within the AVPI binding site, a point mutation was designed which alters the dynamics of flexible loops and blocks PI region of the binding cleft, thus enabling definition of weakly bound small molecules in the AV portion of the binding cleft. Nuclear magnetic resonance analysis confirmed the G306E mutation stabilizes the AV pocket. Biophysical characterization of the mutant confirms conformation change within the PI sub-pocket as evidenced by a significant diminishment in binding affinity of AVPI mimetics, yet the binding affinity of the smaller AV mimetics is maintained or slightly improved in the mutant compared with wild-type. Additional data from non-covalent mass spectrometry analysis shows enhanced binding of AV mimetics to the G306E mutant over the wild-type. The presented data outline a protein engineering strategy that allowed mapping of AV-replacements with better sensitivity and precision. [source] | ||||||||||