Systematic and efficient side chain optimization for molecular docking using a cheapest‐path procedure

Molecular docking of small‐molecules is an important procedure for computer‐aided drug design. Modeling receptor side chain flexibility is often important or even crucial, as it allows the receptor to adopt new conformations as induced by ligand binding. However, the accurate and efficient incorporation of receptor side chain flexibility has proven to be a challenge due to the huge computational complexity required to adequately address this problem. Here we describe a new docking approach with a very fast, graph‐based optimization algorithm for assignment of the near‐optimal set of residue rotamers. We extensively validate our approach using the 40 DUD target benchmarks commonly used to assess virtual screening performance and demonstrate a large improvement using the developed side chain optimization over rigid receptor docking (average ROC AUC of 0.693 vs. 0.623). Compared to numerous benchmarks, the overall performance is better than nearly all other commonly used procedures. Furthermore, we provide a detailed analysis of the level of receptor flexibility observed in docking results for different classes of residues and elucidate potential avenues for further improvement. © 2013 Wiley Periodicals, Inc.     

A concise asymmetric total synthesis of (+)-brevisamide

A new protecting-group-free synthesis of the marine monocyclic ether (+)-brevisamide is reported. The enantioselective synthesis utilizes a key asymmetric Henry reaction and an Achmatowicz rearrangement for the formation of the tetrahydropyran ring. A penultimate Stille cross-coupling allows for an efficient installation of the conjugated (E,E)-diene side chain ultimately delivering (+)-brevisamide.     

Studies toward the synthesis of maoecrystal V

An approach toward the synthesis of maoecrystal V is described. The synthetic strategy for this approach was designed to address unique challenges posed by the strained tetrahydrofuran ring at the center of the target structure.     

Evaluation of several two-step scoring functions based on linear interaction energy, effective ligand size, and empirical pair potentials for prediction of protein-ligand binding geometry and free energy

The performances of several two-step scoring approaches for molecular docking were assessed for their ability to predict binding geometries and free energies. Two new scoring functions designed for "step 2 discrimination" were proposed and compared to our CHARMM implementation of the linear interaction energy (LIE) approach using the Generalized-Born with Molecular Volume (GBMV) implicit solvation model. A scoring function S1 was proposed by considering only "interacting" ligand atoms as the "effective size" of the ligand and extended to an empirical regression-based pair potential S2. The S1 and S2 scoring schemes were trained and 5-fold cross-validated on a diverse set of 259 protein-ligand complexes from the Ligand Protein Database (LPDB). The regression-based parameters for S1 and S2 also demonstrated reasonable transferability in the CSARdock 2010 benchmark using a new data set (NRC HiQ) of diverse protein-ligand complexes. The ability of the scoring functions to accurately predict ligand geometry was evaluated by calculating the discriminative power (DP) of the scoring functions to identify native poses. The parameters for the LIE scoring function with the optimal discriminative power (DP) for geometry (step 1 discrimination) were found to be very similar to the best-fit parameters for binding free energy over a large number of protein-ligand complexes (step 2 discrimination). Reasonable performance of the scoring functions in enrichment of active compounds in four different protein target classes established that the parameters for S1 and S2 provided reasonable accuracy and transferability. Additional analysis was performed to definitively separate scoring function performance from molecular weight effects. This analysis included the prediction of ligand binding efficiencies for a subset of the CSARdock NRC HiQ data set where the number of ligand heavy atoms ranged from 17 to 35. This range of ligand heavy atoms is where improved accuracy of predicted ligand efficiencies is most relevant to real-world drug design efforts.     

Kubo formulas for relativistic fluids in strong magnetic fields

Magnetohydrodynamics of strongly magnetized relativistic fluids is derived in the ideal and dissipative cases, taking into account the breaking of spatial symmetries by a quantizing magnetic field. A complete set of transport coefficients, consistent with the Curie and Onsager principles, is derived for thermal conduction, as well as shear and bulk viscosities. It is shown that in the most general case the dissipative function contains five shear viscosities, two bulk viscosities, and three thermal conductivity coefficients. We use Zubarev’s non-equilibrium statistical operator method to relate these transport coefficients to correlation functions of the equilibrium theory. The desired relations emerge at linear order in the expansion of the non-equilibrium statistical operator with respect to the gradients of relevant statistical parameters (temperature, chemical potential, and velocity.) The transport coefficients are cast in a form that can be conveniently computed using equilibrium (imaginary-time) infrared Green’s functions defined with respect to the equilibrium statistical operator.     

Study of a Stable “Trifluoromethoxide Anion Solution” Arising from 2,4-Dinitro-Trifluoromethoxybenzene

Despite recent advances, trifluoromethoxylation remains a challenging reaction. Here we describe an efficient trifluoromethoxylative substitution, using an inexpensive and easy-to-handle reagent. By mixing DMAP with a slight excess of 1,4-dinitro-trifluoromethoxybenzene ( DNTFB ), a stable solution of trifluoromethoxide anion is obtained and can be used to perform a S_N2 reaction without any silver additives. A precise study of the properties and behavior of this unusual stable solution of CF₃O⁻ species is also performed.     

Adiabatic paths and pseudoholomorphic curves

We consider the (2+1)-dimensional Abelian Higgs model, governed by the GinzburgLandau action functional and describe the adiabatic limit construction for this model. Then we switch to the 4-dimensional case and show that the Taubes correspondence may be considered as a (2+2)-dimensional analogue of the adiabatic limit construction.     

Adiabatic paths and pseudoholomorphic curves

We consider the (2 1)-dimensional Abelian Higgs model, governed by the Ginzburg-Landau action functional and describe the adiabatic limit construction for this model. Then we switch to the 4-dimensional case and show that the Taubes correspondence may be considered as a (2 2)-dimensional analogue of the adiabatic limit construction.     

Bounded and Almost Periodic Solutions of Linear High-Order Hyperbolic Equations

The present paper is devoted to investigating high-order strictly hyperbolic operators with nearly constant coefficients. The invertibility of these operators in spaces of functions uniformly bounded or almost periodic in time is established, provided the symbol of the operator in question has no roots in an open strip containing the real line. Under the additional condition that the strip coincides with a half-plane, exponentially decaying solutions of the nonhomogeneous equation with right-hand side of exponential decay are constructed. In the case of equations with constant coefficients the necessity of the derived conditions is proved. The results of this paper were announced without proofs in [SV].     

Exact controllability in projections for three-dimensional Navier–Stokes equations

The paper is devoted to studying controllability properties for 3D Navier–Stokes equations in a bounded domain. We establish a sufficient condition under which the problem in question is exactly controllable in any finite-dimensional projection. Our sufficient condition is verified for any torus in R³${\mathbb{R}}^3$. The proofs are based on a development of a general approach introduced by Agrachev and Sarychev in the 2D case. As a simple consequence of the result on controllability, we show that the Cauchy problem for the 3D Navier–Stokes system has a unique strong solution for any initial function and a large class of external forces.