Estimation of synthetic accessibility score of drug-like molecules based on molecular complexity and fragment contributions

<p>Abstract</p> <p>Background</p> <p>A method to estimate ease of synthesis (synthetic accessibility) of drug-like molecules is needed in many areas of the drug discovery process. The development and validation of such a method that is able to characterize molecule synthetic accessibility as a score between 1 (easy to make) and 10 (very difficult to make) is described in this article.</p> <p>Results</p> <p>The method for estimation of the synthetic accessibility score (SAscore) described here is based on a combination of fragment contributions and a complexity penalty. Fragment contributions have been calculated based on the analysis of one million representative molecules from PubChem and therefore one can say that they capture historical synthetic knowledge stored in this database. The molecular complexity score takes into account the presence of non-standard structural features, such as large rings, non-standard ring fusions, stereocomplexity and molecule size. The method has been validated by comparing calculated SAscores with ease of synthesis as estimated by experienced medicinal chemists for a set of 40 molecules. The agreement between calculated and manually estimated synthetic accessibility is very good with <it>r</it>²= 0.89.</p> <p>Conclusion</p> <p>A novel method to estimate synthetic accessibility of molecules has been developed. This method uses historical synthetic knowledge obtained by analyzing information from millions of already synthesized chemicals and considers also molecule complexity. The method is sufficiently fast and provides results consistent with estimation of ease of synthesis by experienced medicinal chemists. The calculated SAscore may be used to support various drug discovery processes where a large number of molecules needs to be ranked based on their synthetic accessibility, for example when purchasing samples for screening, selecting hits from high-throughput screening for follow-up, or ranking molecules generated by various <it>de novo </it>design approaches.</p

The Adsorption of Atomic Nitrogen on Ru(0001): Geometry and Energetics

The local adsorption geometries of the (2x2)-N and the (sqrt(3)x sqrt(3))R30^o -N phases on the Ru(0001) surface are determined by analyzing low-energy electron diffraction (LEED) intensity data. For both phases, nitrogen occupies the threefold hcp site. The nitrogen sinks deeply into the top Ru layer resulting in a N-Ru interlayer distance of 1.05 AA and 1.10 AA in the (2x2) and the (sqrt(3)x sqrt(3))R30^o unit cell, respectively. This result is attributed to a strong N binding to the Ru surface (Ru--N bond length = 1.93 AA) in both phases as also evidenced by ab-initio calculations which revealed binding energies of 5.82 eV and 5.59 eV, respectively.Comment: 17 pages, 5 figures. Submitted to Chem. Phys. Lett. (October 10, 1996

Vibrations, coverage, and lateral order of atomic nitrogen and formation of NH₃ on Ru(10̅̅10)

The dissociative chemisorption of nitrogen on the Ru(10̅10) surface has been studied using high-resolution electron energy loss spectroscopy (HREELS), thermal desorption spectroscopy (TDS) and low-energy electron diffraction (LEED). To prepare a surface covered by atomic nitrogen we have used ionization-gauge assisted adsorption. A saturation coverage of θN=0.6 is achieved of which about 30% is in the subsurface region. At saturation coverage a (-1/2 1/1) pattern is observed. Then v ǁ(Ru–N) mode at 41 meV and the v_l_(Ru–N) mode at 60 meV are identified. Upon exposing the nitrogen covered surface to hydrogen at 300 K we have observed the formation of NH3 which is characterized by its symmetric bending mode δs(NH3) at 149 meV. At 400 K, NH3 could not be detected. The reaction intermediate NH is stable up to 450 K and has been identified by its vibrational losses ν(Ru–NH) at 86 meV, and ν(N–H) at 408 meV. The TD spectra of mass 14 show three desorption states of nitrogen, Nα at 740 K (from subsurface N), Nβ shifting from 690 to 640 K with increasing coverage, and Nϒ at 550 K. The activation energy for desorption via the Nβ state is 120±10 kJ/mol. The TD spectra of mass two showed three desorption states at 450, 550, and 650 K due to the decomposition of NHx

Coverage, lateral order, and vibrations of atomic nitrogen on Ru(0001)

The N/Ru(0001) system was studied by thermal desorption spectroscopy (TDS), low‐energy electron diffraction (LEED), and high‐resolution electron energy‐loss spectroscopy (HREELS). Atomic nitrogen was prepared by NH3 decomposition at sample temperatures decreasing from 500 to 350 K during NH3 exposure. A maximum N coverage of θN=0.38 could thus be achieved. ∛, split 2×2 and 2×2 LEED patterns were observed for decreasing θN. After NH3 decomposition and before annealing the sample to a temperature above 400 K, the surface is composed of adsorbed N, H, and NH species. This composite layer exhibits a split ∛ LEED pattern due to domains of size 4 with heavy walls. This phase decays through dissociation of NH leading to sharp first‐order type desorption peaks of H2 and N2. From the weak intensity of the ν(Ru–NH) stretch mode it is concluded that NH is adsorbed at threefold‐hollow sites. The energy of the ν(Ru–N) mode shifts from 70.5 to 75.5 meV when θN is increased from 0.25 to 0.38

Dual-Path Mechanism for Catalytic Oxidation of Hydrogen on Platinum Surfaces

The catalytic formation of water from adsorbed hydrogen and oxygen atoms on Pt(111) was studied with scanning tunneling microscopy and high resolution electron energy loss spectroscopy. The known complexity of this reaction is explained by the strongly temperature dependent lifetime of the product H2O molecules on the surface. Below the desorption temperature water reacts with unreacted O adatoms to OHad, leading to an autocatalytic process; at higher temperatures sequential addition of H adatoms to Oad with normal kinetics takes place

Adsorbate-induced electronic modification of alkali-metal overlayers

For submonolayer coverages of Cs on Ru(0001) surfaces, the Cs-Ru vibration is observed at 7.8 meV (63 cm−1) by means of high-resolution electron-energy-loss spectroscopy. At Cs coverages near the complete monolayer the adlayer becomes metallic as indicated by screening of the Cs-Ru vibration and the occurrence of an electronic excitation (plasmon) at 580 meV. Coadsorption of CO as well as of oxygen leads to the reappearance of the Cs-Ru vibration and the disappearance of the electronic excitation which is interpreted as a demetallization through chemical interaction with the coadsorbed species

Sticking coefficient for dissociative adsorption of N₂ on Ru single‐crystal surfaces

The dissociative chemisorption of N2 on Ru(0001), Ru(101̄0), and Ru(112̄1) surfaces at 300 K was studied by means of high‐resolution electron energy loss spectroscopy and thermal desorption spectroscopy. The initial sticking coefficient was determined to s0=(1±0.8)×10−12, within the limits of error independent of surface orientation. On Ru(101̄0) and Ru(112̄1) small amounts of N can be dissolved into the subsurface region

The oxidation of CO on RuO₂(110) at room temperature

RuO2(110) surfaces were prepared by exposing Ru(0001) to 10(7) L of O-2 at 700 K. Postexposure of O-2 at 300 K resulted in an additional oxygen species (O-cus) adsorbed on coordinatively unsaturated Ru atoms (Ru-cus). The surface was then exposed to CO at 300 K and studied by thermal desorption spectroscopy (TDS) and high-resolution electron energy loss spectroscopy (HREELS). It is demonstrated that CO is oxidized at 300 K through reaction with both the O-cus as well as with surface O-atoms held in bridge positions (O-bridge). Although-at room temperature-CO adsorbs intermediately on the Ru-cus atoms, it is stable only at the Ru atoms underneath the O-bridge after the latter has been reacted off. At room temperature only surface oxygen takes part in the CO oxidation and the oxygen-depleted surface can be restored by O-2 exposure, so that under steady-state flow conditions an oxygen-deficient surface will exist whose stoichiometry will be determined by the ratio of partial pressures