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We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X-ray crystallography to reveal the binding mode of an antagonist series to the A2A adenosine receptor (AR). Eight A2AAR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A2AAR were experimentally determined and investigated through a cycle of ligand-FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X-ray crystallography of the A2AAR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A2AAR, an emerging target in immuno-oncology.  相似文献   
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Let S be a semigroup. We study the structure of graded-simple S-graded algebras A and the exponential rate PIexp S-gr(A):= limn→∞ \(\sqrt[n]{{c_n^{S - gr}\left( A \right)}}\) of growth of codimensions c n S-gr (A) of their graded polynomial identities. This is of great interest since such algebras can have non-integer PIexp S-gr(A) despite being finite dimensional and associative. In addition, such algebras can have a non-trivial Jacobson radical J(A). All this is in strong contrast with the case when S is a group since in the group case J(A) is trivial, PIexp S-gr(A) is always integer and, if the base field is algebraically closed, then PIexp S-gr(A) equals dimA. Without any restrictions on the base field F, we classify graded-simple S-graded algebras A for a class of semigroups S which is complementary to the class of groups. We explicitly describe the structure of J(A) showing that J(A) is built up of pieces of a maximal S-graded semisimple subalgebra of A which turns out to be simple. When F is algebraically closed, we get an upper bound for \({\overline {\lim } _{n \to \infty }}\sqrt[n]{{c_n^{S - gr}\left( A \right)}}\). If A/J(A) ≈ M 2(F) and S is a right zero band, we show that this upper bound is sharp and PIexp S-gr(A) indeed exists. In particular, we present an infinite family of graded-simple algebras A with arbitrarily large non-integer PIexp S-gr(A).  相似文献   
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A. Dooms  E. Jespers 《代数通讯》2013,41(9):2879-2888
In this article we construct free groups and subgroups of finite index in the unit group of the integral group ring of a finite non-Abelian group G for which every nonlinear irreducible complex representation is of degree 2 and with commutator subgroup G′ a central elementary Abelian 2-group.  相似文献   
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Several aspects of relations between braces and non-degenerate involutive set-theoretic solutions of the Yang–Baxter equation are discussed and many consequences are derived. In particular, for each positive integer n a finite square-free multipermutation solution of the Yang–Baxter equation with multipermutation level n and an abelian involutive Yang–Baxter group is constructed. This answers a problem of Gateva-Ivanova and Cameron. It is proved that finite non-degenerate involutive set-theoretic solutions of the Yang–Baxter equation whose associated involutive Yang–Baxter group is abelian are multipermutation solutions. Earlier the authors proved this with the additional square-free hypothesis on the solutions. It is also proved that finite square-free non-degenerate involutive set-theoretic solutions associated to a left brace are multipermutation solutions.  相似文献   
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Eric Jespers 《代数通讯》2013,41(12):3603-3608
We compute the extended centroid of a prime ring graded by an abelian group.  相似文献   
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