Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibi...Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibitors a very interesting challenge in medicinal chem- istry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship （3D-QSAR）, molecular docking, molecular dy- namics （MD） simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T3151. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T3151 activities were designed and presented to experimenters for reference.展开更多
Jan Lukasiewicz acknowledged that Aristotle＇s syllogistic does not admit singular terms and presents syllogism as an implication. But he failed to recognize syllogistic necessity, reducing this necessity to ＂formal ...Jan Lukasiewicz acknowledged that Aristotle＇s syllogistic does not admit singular terms and presents syllogism as an implication. But he failed to recognize syllogistic necessity, reducing this necessity to ＂formal implication＂ as introduced by Russell, when Aristotle shows it as binding relations between three terms. On the contrary, Paul Lorenzen directly recognized syllogistic necessity as the typical example of his own logical implication. His reconstruction of syllogistic differs from the original by his interpretation of particular propositions as the determination of classes which are specified by predicates. The result is the representation of valid moods as the board of all multiplications of relations which are permitted. These relations are not only the Aristotelian ,4, E,I, O, but also the new converse asymmetrical relations of A and O： （a） and （o）.展开更多
This paper addresses the issues of conservativeness and computational complexity of probabilistie robustness analysis. The authors solve both issues by defining a new sampling strategy and robustness measure. The new ...This paper addresses the issues of conservativeness and computational complexity of probabilistie robustness analysis. The authors solve both issues by defining a new sampling strategy and robustness measure. The new measure is shown to be much less conservative than the existing one. The new sampling strategy enables the definition of efficient hierarchical sample reuse algorithms that reduce significantly the computational complexity and make it independent of the dimension of the uncertainty space. Moreover, the authors show that there exists a one to one correspondence between the new and the existing robustness measures and provide a computationally simple algorithm to derive one from the other.展开更多
文摘Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibitors a very interesting challenge in medicinal chem- istry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship （3D-QSAR）, molecular docking, molecular dy- namics （MD） simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T3151. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T3151 activities were designed and presented to experimenters for reference.
文摘Jan Lukasiewicz acknowledged that Aristotle＇s syllogistic does not admit singular terms and presents syllogism as an implication. But he failed to recognize syllogistic necessity, reducing this necessity to ＂formal implication＂ as introduced by Russell, when Aristotle shows it as binding relations between three terms. On the contrary, Paul Lorenzen directly recognized syllogistic necessity as the typical example of his own logical implication. His reconstruction of syllogistic differs from the original by his interpretation of particular propositions as the determination of classes which are specified by predicates. The result is the representation of valid moods as the board of all multiplications of relations which are permitted. These relations are not only the Aristotelian ,4, E,I, O, but also the new converse asymmetrical relations of A and O： （a） and （o）.
基金supported in part by grants from NASA (NCC5-573)LEQSF (NASA /LEQSF(2001-04)-01)+1 种基金the NNSFC Young Investigator Award for Overseas Collaborative Research (60328304)a NNSFC grant (10377004)
文摘This paper addresses the issues of conservativeness and computational complexity of probabilistie robustness analysis. The authors solve both issues by defining a new sampling strategy and robustness measure. The new measure is shown to be much less conservative than the existing one. The new sampling strategy enables the definition of efficient hierarchical sample reuse algorithms that reduce significantly the computational complexity and make it independent of the dimension of the uncertainty space. Moreover, the authors show that there exists a one to one correspondence between the new and the existing robustness measures and provide a computationally simple algorithm to derive one from the other.
