A pseudo-ligand approach to virtual screening

A virtual screening method is presented that is grounded on a receptor-derived pharmacophore model termed "virtual ligand" or "pseudo-ligand". The model represents an idealized constellation of potential ligand sites that interact with residues of the binding pocket. For rapid virtual screening of compound libraries the potential pharmacophore points of the virtual ligand are encoded as an alignment-free correlation vector, avoiding spatial alignment of pharmacophore features between the pharmacophore query (i.e., the virtual ligand) and the candidate molecule. The method was successfully applied to retrieving factor Xa inhibitors from a Ugi three-component combinatorial library, and yielded high enrichment of actives in a retrospective search for cyclooxygenase-2 (COX-2) inhibitors. The approach provides a concept for "de-orphanizing" potential drug targets and identifying ligands for hitherto unexplored or allosteric binding pockets.     

PhAST: pharmacophore alignment search tool

We present a ligand-based virtual screening technique (PhAST) for rapid hit and lead structure searching in large compound databases. Molecules are represented as strings encoding the distribution of pharmacophoric features on the molecular graph. In contrast to other text-based methods using SMILES strings, we introduce a new form of text representation that describes the pharmacophore of molecules. This string representation opens the opportunity for revealing functional similarity between molecules by sequence alignment techniques in analogy to homology searching in protein or nucleic acid sequence databases. We favorably compared PhAST with other current ligand-based virtual screening methods in a retrospective analysis using the BEDROC metric. In a prospective application, PhAST identified two novel inhibitors of 5-lipoxygenase product formation with minimal experimental effort. This outcome demonstrates the applicability of PhAST to drug discovery projects and provides an innovative concept of sequence-based compound screening with substantial scaffold hopping potential.     

Automated De Novo Drug Design: Are We Nearly There Yet?

Medicinal chemistry and, in particular, drug design have often been perceived as more of an art than a science. The many unknowns of human disease and the sheer complexity of chemical space render decision making in medicinal chemistry exceptionally demanding. Computational models can assist the medicinal chemist in this endeavour. Provided here is an overview of recent examples of automated de novo molecular design, a discussion of the concepts and computational approaches involved, and the daring prediction of some of the possibilities and limitations of drug design using machine intelligence.     

Ground state spectroscopic constants of H15NCS,HN13CS,and HNC34S,and the molecular structure of isothiocyanic acid

The rotational spectrum of isothiocyanic acid was measured for the isotopically enriched species H¹⁵NCS and HN¹³CS as well as HNC³⁴S in natural abundance. In the frequency range from 8 to 240 GHz the a-type R-branch transitions were measured for all three isotopic species. The ^qQ₁ transitions were identified in the microwave region for H¹⁵NCS and HN¹³CS. The rotational and centrifugal distortion constants were determined using Watson's Hamiltonian in the S reduction, extended empirically to higher order terms in the angular momentum. The molecular structure of isothiocyanic acid was reevaluated using a modified substitution method and the NCS chain was found to be bent: $\text{r(}\text{NH}\text{) = 0.993}\text{A}\text{?}$, $\text{r(}\text{NC}\text{) = 1.207}\text{A}\text{?}$, $\text{r(}\text{CS}\text{) = 1.5665}\text{A}\text{?}$, ∠HNC = 131.7°, and ∠NCS = 173.8°. The molecule has the trans conformation.     

Rotational Spectra of the Thiosulfeno Radical, HSS and DSS, between 0.3 and 0.9 THz

The rotational spectra of the HSS and DSS radicals were studied in selected regions between 331 and 883 GHz. The radicals were produced by discharging a gaseous mixture of hydrogen (or deuterium) and hydrogen sulfide in the cell. The observation of the b-type Q-branch and R-branch lines with K(a) = 2-1 and 3-2 for HSS and DSS, respectively, as well as the a-type R-branch lines allowed the improvement and the determination of the molecular constants among them (in MHz) We have reevaluated the harmonic force field of HSS and the ground state average and approximate equilibrium structural parameters. For the latter, we obtained r(HS) = 135.23 pm, r(SS) = 196.03 pm, and angle = 101.74 degrees. These results are compared with those from previous and own quantum chemical calculations as well as with results of related molecules. Copyright 2000 Academic Press.     

The torsion-rotation microwave spectrum of 12CH318OH and the structure of methanol

The microwave and millimeter wave spectrum of ¹²CH₃¹⁸OH has been observed in the frequency region 7.9–200 GHz. Both a- and b-type transitions have been assigned and measured. This spectrum was analyzed using the method of Lees and Baker, and rotational constants, torsional constants, centrifugal distortion constants, the barrier to internal rotation and moments of inertia have been evaluated. The barrier has been found to be 374.91 ± 0.18 cm^?1, in good agreement with that of ¹²CH₃¹⁶OH. The moments of inertia were combined with those of other isotopic species to give a full substitution structure. To assist searches for this molecule in interstellar space a table of predicted frequencies of astrophysically interesting transitions is presented.     

Bestimmung des elektrischen Kernquadrupolmomentes des ungeraden stabilen Strontium-87-Kerns

In order to determine the electric quadrupole moment of Sr⁸⁷ (I= 9/2) the hyperfine structure-splitting of the 5s5p ³ P ₁-state of the SrI-spectra was investigated by optical double resonance. By detection of high frequency transitions (ΔF=±1,Δm _F=0,±1) in an external magnetic fieldH ₀≈0 one obtains the hyperfine structure separations asv _F=11/2?F=9/2=1463·149 (6) Mc/sec andv _F=9/2?F=7/2=1130·264 (6) Mc/sec. From these frequencies one calculates the magnetic hyperfine structure-splitting constantA=?260·084 (2) Mc/sec and the electric quadrupole interaction constantB=?35·658 (6) Mc/sec. B leads to an electric quadrupole moment ofQ(Sr⁸⁷)=+0·36 (3)·10^?24 cm².