Pharmacophore-based database mining for probing fragmental drug-likeness of diketo acid analogues

A number of the structurally diverse chemical compounds with functional diketo acid (DKA) subunit(s) have been revealed by combined online and MoStBiodat 3D pharmacophore-guided ZINC and PubChem database screening. We used the structural data available from such screening to analyse the similarities of the compounds containing the DKA fragment. Generally, the analysis by principal component analysis and self-organizing neural network approaches reveals four families of compounds complying with the chemical constitution (aromatic, aliphatic) of the compounds. From a practical point of view, similar studies may reveal potential bioisosteres of known drugs, e.g. raltegravir/elvitegravir. In this context, it seems that mono-halogenated aryl substructures with para group show the closest similarity to these compounds, in contrast to structures where the aromatic ring is halogenated in both ortho- and para-locations.     

In pursuit of nanocarbons

With the advent of the Krätschmer‐Huffman historical breakthrough on the macroscopic synthesis of C₆₀ in the late summer of 1990, I decided to stop all my research so far in the area of spectroscopy of gas‐phase molecular microclusters. Since then, my odyssey in and quest for the so‐called nanocarbons started. Thanks to the brand‐new and enchanting world of fullerenes, metallofullerenes, carbon nanotubes and nano‐peapods, I have been able to entertain (and still am entertaining!) “the pleasure of finding things out”, as Richard Feynman once put it in an interview by a BBC television program in 1981. I believe that as long as one has big dreams and lays the groundwork for the dreams, one will achieve them. My quest for nanocarbons is still on its way. DOI 10.1002/tcr.201100037     

Evaluating uncertainty in analytical measurements: the pursuit of correctness

 Simple in principle, the evaluation of uncertainty, especially in chemical analysis, is not a routine task and needs great care to be correct. This can be seen, particularly, from an examination of the EURACHEM Guide, Quantifying Uncertainty in Analytical Measurement (1995), which is the most important document on the subject. The examination reveals, in the author's opinion, a shortage of correctness in some principal details of the uncertainty estimation process as presented in worked examples in the Guide, and the author has therefore formulated some "in pursuit of correctness" rules for estimating uncertainty. The rules and respective comments are concerned with the following items: (1) choosing an appropriate distribution function in type B evaluation of uncertainty, (2) the necessity for consideration of separate contributions to the combined uncertainty, and (3) taking account of actual influence factors in the uncertainty estimation process. Furthermore, the problem of estimation of conditional versus overall uncertainty is touched upon in connection with comparative trials where only internal consistency of results is required. Received: 29 January 1998 · Accepted: 10 February 1998     

ALOHA: a novel probability fusion approach for scoring multi-parameter drug-likeness during the lead optimization stage of drug discovery

Automated lead optimization helper application (ALOHA) is a novel fitness scoring approach for small molecule lead optimization. ALOHA employs a series of generalized Bayesian models trained from public and proprietary pharmacokinetic, absorption, distribution, metabolism, and excretion, and toxicology data to determine regions of chemical space that are likely to have excellent drug-like properties. The input to ALOHA is a list of molecules, and the output is a set of individual probabilities as well as an overall probability that each of the molecules will pass a panel of user selected assays. In addition to providing a summary of how and when to apply ALOHA, this paper will discuss the validation of ALOHA’s Bayesian models and probability fusion approach. Most notably, ALOHA is demonstrated to discriminate between members of the same chemical series with strong statistical significance, suggesting that ALOHA can be used effectively to select compound candidates for synthesis and progression at the lead optimization stage of drug discovery.     

New functionals for correlation energy deduced in the framework of the correlation factor approach

The general characteristics of two-body density functionals (TBDF) are explored and two new correlation energy functionals are derived using the correlation factor approach. The optimization of the parameters entering the above functionals requires exact and accurate atomic correlation energies (ACE). We revised the ACE values in the literature and obtained a new set of “exact” ACE for atoms with 2 ≤ Z ≤ 10. Unfortunately, there exist some inaccuracies in the ACE values of the second-row atoms, which make unsuitable the inclusion of them in the optimization. The ACE calculated for the first period with the above functionals, using the optimized sets of parameters, are in excellent agreement with the exact ones, while the corresponding values calculated for the second-row atoms are between the precision margins estimated by us for the exact values. © 1997 John Wiley & Sons, Inc.     

Electron correlation forms in the LiH molecule—fermi correlation

Correlation forms for electrons of the same spin small molecules are analyzed by taking the LiH molecule as an example. The analyses are carried out on the basis of the reduced density matrix theory and for both the ground state and the first excited state. It turns out that although there is a certain similarity, the correlated motions of parallel-spin electrons in this four-electron molecule are more complicated than those found for the two-electron molecule. The correlation forms are not always constant. They vary essentially from one state to another, but are insensitive to fairly large changes of the internuclear distance for a given state.     

Multi-targeted molecular docking,drug-likeness and ADMET studies of derivatives of few quinoline- and acridine-based FDA-approved drugs for anti-breast cancer activity

Structural Chemistry - Quinoline- and acridine-based drugs are widely used as anti-breast cancer agents. These drugs act through various mechanisms of action; for example, neratinib acts on...     

Development of oxopyrrolidine-based anti-cancer compounds: DNA binding, in silico, cell line studies, drug-likeness and mechanism at supra-molecular level

Due to an increasing demand for effective anti-cancer drugs, an oxopyrrolidine-based ligand, sodium 1-(3-(2-aminoethylamino)propyl)-5-oxopyrrolidine-2-carboxylate, was synthesised by the sodium hydride-assisted coupling of pyroglutamic acid with 1,3-diiodopropane under a nitrogen atmosphere. The intermediate thus formed was allowed to react with ethylenediamine in acetonitrile. The ligand formed individual complexes with Cu(II) and Ni(II) metal ions, respectively. The complexes were relatively resistant to degradation in PBS at physiological pH. The DNA-binding constants (K _b) for the ligand, copper and nickel complexes were 2.09 × 104 M^-1, 2.37 × 104 M^-1 and 2.11 × 104 M^-1, respectively, revealing the strong binding of these complexes with DNA. Haemolysis assays indicated that the ligand and its complexes were less toxic to rabbit RBCs than doxorubicin. Lipinski’s parameters calculated for the reported compounds indicated their good oral bioavailability. All the compounds exhibited good activities towards MCF-7 (wild type) cancer cell lines. The results of in silico studies, DNA-binding and anti-cancer activities indicated that the reported compounds might be interacting with DNA as one of their possible mechanisms of action.     

A facile synthesis,drug-likeness,and in silico molecular docking of certain new azidosulfonamide–chalcones and their in vitro antimicrobial activity

Monatshefte für Chemie - Chemical Monthly - New azidosulfonamide–chalcone derivatives were designed and synthesized. Their structures were elucidated by 1H and 13C NMR spectral analyses,...     

A density functional for the correlation energy,deduced in the framework of the correlation factor approach

An approximate density functional is deduced from a wave function within the correlation factor method. The new functional does not include terms depending on the gradient of the density, but shows the simplicity of local density functionals without spin polarization. However, it includes correctly the inhomogeneity effects and, also, the nonlocal nature of an electronic system. The approach adopted here stresses the goodness of the expression taken by Colle and Salvetti for building a correlation factor and, at the same time, allows us to gain light on the nature of the deficiencies of those functionals obtained, up to now, from the perspective of the Hohenberg and Kohn theorem.     

Developing countries in pursuit of analytical quality control: the need for appropriate reference materials

Summary In a special session dedicated to problems of Analytical Quality Assurance (AQA) in Developing Countries (DC), the participants of BERM-5 had an opportunity to hear of the difficulties routinely encountered in many laboratories in these countries. Participants from Chile, China, Ghana, India, Korea, Malaysia, Philippines, Sri Lanka, and Thailand were invited to share the platform during this special session. The salient features of discussions that took place are summarized in this report and will not therefore be reported elsewhere.     

Development of a method for evaluating drug-likeness and ease of synthesis using a data set in which compounds are assigned scores based on chemists' intuition

The concept of drug-likeness, an important characteristic for any compound in a screening library, is nevertheless difficult to pin down. Based on our belief that this concept is implicit within the collective experience of working chemists, we devised a data set to capture an intuitive human understanding of both this characteristic and ease of synthesis, a second key characteristic. Five chemists assigned a pair of scores to each of 3980 diverse compounds, with the component scores of each pair corresponding to drug-likeness and ease of synthesis, respectively. Using this data set, we devised binary classifiers with an artificial neural network and a support vector machine. These models were found to efficiently eliminate compounds that are not drug-like and/or hard-to-synthesize derivatives, demonstrating the suitability of these models for use as compound acquisition filters.     

In pursuit of pestalotiopsin a via zirconocene-mediated ring contraction

[reaction: see text] An asymmetric route from the epimeric beta-hydroxy esters 4 and 5 to the densely functionalized (+)-10 and (-)-10, respectively, is described. Either cyclobutanol can be made available as the predominant product. The levorotatory antipode has been transformed into the advanced intermediate 21 bearing side chains destined to become incorporated into the cyclononene ring of the title compound (1).     

Divide-and-conquer local correlation approach to the correlation energy of large molecules

A divide-and-conquer local correlation approach for correlation energy calculations on large molecules is proposed for any post-Hartree-Fock correlation method. The main idea of this approach is to decompose a large system into various fragments capped by their local environments. The total correlation energy of the whole system can be approximately obtained as the summation of correlation energies from all capped fragments, from which correlation energies from all adjacent caps are removed. This approach computationally achieves linear scaling even for medium-sized systems. Our test calculations for a wide range of molecules using the 6-31G or 6-31G( * *) basis set demonstrate that this simple approach recovers more than 99.0% of the conventional second-order Moller-Plesset perturbation theory and coupled cluster with single and double excitations correlation energies.     

Electron correlation effects in the Fe dimer

The potential energy surface of the Fe dimer is investigated on the basis of density functional theory in the generalized gradient approximation (GGA). Electron correlation effects are taken into account explicitly within the GGA+U approach. We find a value of 2.20 eV for the Coulomb repulsion parameter U to describe the Fe dimer best, yielding a 9 Sigma(g)- ground state with an interatomic separation of 2.143 A. Agreement of the associated vibrational frequency, binding energy, ionization potential, and electron affinity with experimental data as well as corresponding results calculated within a high-level ab initio approach is improved significantly compared to conventional GGA. The effect of U on calculated geometric and magnetic properties of larger Fe clusters is discussed.