Gerald M Maggiora - Academia.edu (original) (raw)

Papers by Gerald M Maggiora

Methods and principles in medicinal chemistry, Jan 26, 2005

Journal of the American Chemical Society, Dec 1, 1973

Biopolymers, 1994

Microtubules, which play many diverse and important roles in biological systems, are usually made... more Microtubules, which play many diverse and important roles in biological systems, are usually made up of 13 nearly axial protofilaments formed from individual tubulin molecules. In this paper, a nonlinear dynamic model has been developed to elucidate the mechanism of the internal motion occurring during the assembly of microtubules. The results derived from the model indicate that such internal motion is associated with a solitary wave, or kink, excited by the energy released from the hydrolysis of GTP-->GDP in microtubular solutions. As the kink moves forward, the individual tubulin molecules involved in the kink undergo motions that can be likened to the dislocation of atoms within the crystal lattice. Thus, the dynamic instability of microtubules may be characterized by a series of dislocation motions of the tubulin molecules. An energy estimate shows that a kink in the system possesses about 0.36-0.44 eV, which is quite close to but smaller than the 0.49 eV of energy released from the hydrolysis of GTP. Therefore, the relevant energy derived from our model is fully consistent with experimental observations; this finding also suggests that the hydrolysis energy may be responsible for exciting the solitary wave, or kink, leading to tubulin dislocation in microtubules. Our model, and its intrinsic properties, i.e., dynamic nonlinearity, thermodynamic irreversibility, as well as an energy input from a sustained source, implies that the growth of microtubules is a typical dissipative process and that their structure in vivo is typical of dissipative structures.

Journal of Medicinal Chemistry, Aug 21, 2004

Medicinal chemists are frequently asked to review lists of compounds to assess their drug-or lead... more Medicinal chemists are frequently asked to review lists of compounds to assess their drug-or leadlike nature and to evaluate the suitability of lead compounds based on their "attractiveness" and/or synthetic feasibility as a basis for launching a drug-discovery campaign. It is often felt that one medicinal chemist's opinion is as good as any other, but is it? In an attempt to answer this question, an experiment was performed in conjunction with a recent compound acquisition program (CAP) conducted at Pharmacia. Historically, the CAP included a review of many thousands of compounds by medicinal chemists who eliminate anything deemed undesirable for any reason. In a review conducted in 2002, about 22 000 compounds requiring review by medicinal chemists were broken down into 11 lists of approximately 2000 compounds each. Unknown to the medicinal chemists, a subset of 250 compounds, previously rejected by a very experienced senior medicinal chemist, was added to each of the lists. Most of the 13 medicinal chemists who participated in this process reviewed two lists, although some only reviewed a single list and one reviewed three lists. Those compounds that were deemed unacceptable were recorded and tabulated in various ways to assess the consistency of the reviews. It was found that medicinal chemists were not very consistent in the compounds they rejected as being undesirable. The inconsistency arises from the subjective analysis that all humans utilize when considering "data sets" of any kind. This has important implications for pharmaceutical project teams where individual medicinal chemists review lists of primary screening hits to identify those compounds suitable for follow-up. Once a compound is removed from a list, it and other structurally similar compounds are effectively removed from further consideration. This can also have an impact on computational chemists who are developing models for assessing the desirability or attractiveness of different classes of compounds for lead discovery.

Supplementary Methods - TERT Promoter Genotyping

Chemischer Informationsdienst, Jan 20, 1981

Journal of Chemical Physics, Feb 1, 1986

The ground and excited electronic states of a magnesium porphyrin–porphyrin (MgP–P) dimer in a va... more The ground and excited electronic states of a magnesium porphyrin–porphyrin (MgP–P) dimer in a variety of geometries have been investigated by ab initio configuration interaction calculations. The lowest four excited singlet states were found to be locally excited monomer-like (π, π*) states in each geometry, except for dimers in which the macrocycles were constrained to lie within the van der Waals separation. The lowest MgP+–P− radical pair state CT1 was found much higher in energy than the lowest (π, π*) state; CT1←S0 transition energies varied approximately linearly with macrocyclic center-to-center distance, but were only weakly affected by relative macrocyclic orientation. Coordination of the Mg atom by chloride ion was shown to differentially stabilize CT1 relative to (π, π*) states, to the extent that CT1 is positioned near or below the lowest (π, π*) state. Moreover, estimates of the differential stabilization of CT1 by a polarizable medium suggest that combined point-charge and medium effects are sufficient to stabilize CT1 below the lowest (π, π*) state in a variety of geometries of the complex.

Journal of Chemical Information and Modeling, Jul 1, 2006

Chemischer Informationsdienst, Feb 14, 1978

Chemischer Informationsdienst, Mar 22, 1977

ChemInform Abstract (Geometrieoptimierungen für SO32-, HSO3-und cis-sowie trans-SO2OH-;Berücksich... more ChemInform Abstract (Geometrieoptimierungen für SO32-, HSO3-und cis-sowie trans-SO2OH-;Berücksichtigung der Umgebungen von SO32-und HSO3-im festen Zustand durch Einbeziehung des Kristallfeldes in die Rechnungen)

The conception of potent therapeutical agents relies on the knowledge of the interaction mode bet... more The conception of potent therapeutical agents relies on the knowledge of the interaction mode between the ligands and their receptor sites. However, very often, the direct study of these interactions is difficult as the three-dimensional (3D) structure of the receptor sites is not completely known. Consequently, an indirect approach resides in the comparison of the ligands of interest on the basis of their physico-chemical properties, in such a way to deduce the nature of their common molecular sites involved in the binding to the macromolecule and/or responsible for their particular activity.

Molecules, Dec 7, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

International Journal of Quantum Chemistry, Jun 18, 2009

ABSTRACT Wave functions for the ground state and low-lying 1,3(n→*) and 1,3(π→π*) excited states ... more ABSTRACT Wave functions for the ground state and low-lying 1,3(n→*) and 1,3(π→π*) excited states of pyrazine are obtained from a configuration interaction procedure based on molecular orbitals from a ground-state SCF calculation. A detailed comparison is made between the present results and both experimental data and more extensive calculations, indicating that the qualitative ordering of excited states predicted here is substantially correct. Expansion coefficients of the principal configurations for most excited states resemble closely those of more accurate calculations, and for excited states where Franck-Condon transition energies are known, a linear relationship between experimental and computed transition energy values is obtained. These observations, as well as the favorable computational characteristics of the molecular fragment approach, indicate that the techniques used on pyrazine are well suited for studies of the spectra of large molecules.

Springer eBooks, 2014

The size of the chemical universe of small organic molecules is estimated to be around 200 billio... more The size of the chemical universe of small organic molecules is estimated to be around 200 billion, and its true size may be even larger. Because the size of “representative” subsets of that universe can still be substantial, computer-based methods are required to capture, manage, and search the massive amount of available chemical information associated with these molecules. This has given rise to the field of chemical informatics. Three concepts play major roles in this field, two of which, molecular similarity and chemical space (CS), are dealt with in this chapter. Of the two, molecular similarity is the more fundamental since it plays a crucial role in the definition of CS itself. The third concept, activity and property landscapes, while important, will not be considered here. Though the potentially relevant subset of molecules that is applicable in food science applications is considerably smaller than the universe of small organic molecules, it nonetheless is large enough to benefit from concepts of molecular similarity and CS that have proved useful in medicinal chemistry and related fields of chemistry. The present chapter provides a relatively detailed and somewhat didactic description of the two concepts, how they are implemented, and how they can be applied in typical chemical applications.

Methods of biochemical analysis, Oct 31, 2006

Journal of Mathematical Chemistry, Jul 1, 2005

A methodology, derived by analogy to Shannon's information-theoretic theory of communication and ... more A methodology, derived by analogy to Shannon's information-theoretic theory of communication and utilizing the concept of mutual information, has been developed to characterize partitioned property spaces. A family of non-intersecting subsets that cover the "universe" of objects represents a partitioned property space. Each subset is thus an equivalence class. A partition and it's associated equivalence classes can be generated using any one of a number of procedures including hierarchical and non-hierarchical clustering, direct approaches using rough set methods, and cell-based partitioning, to name a few. Thus, partitioned property spaces arise in many instances and represent a very large class of problems. The approach is based on set-valued mappings from equivalence classes in one partition to those in another and provides a coarse-grained means for comparing property spaces. From these mappings it is possible to compute a number of Shannon entropies that afford calculation of mutual information, which represents that amount of information shared by two partitions of a set of objects. Taking the ratio of the mutual information with the maximum possible mutual information yields a quantity that measures the similarity of the two partitions. While the focus in this work is directed towards small sets of objects the approach can be extended to many more classes of problems that can be put into a similar form, which includes many types of cheminformatic and biological problems. A number of scenarios are presented that illustrate the concept and indicate the broader class of problems that can be handled by this method.

Springer eBooks, Feb 22, 2008

Chemical Physics Letters, Apr 1, 1982

Ab initio restricted Harrree-rock sclf-consistcnt-Iield molecular orbits1 calculations at the STO... more Ab initio restricted Harrree-rock sclf-consistcnt-Iield molecular orbits1 calculations at the STO-3G and J-31C baas set levels have been used to determme the mimmum-rnergy ~IIUC~UIC oiduorrogen pcntokidc, NzOj-The c~cuht~oos~ho~v that NaOs has an anhydride-type structure wth its mtro groups rotated 42' out of the ccnkd NO -N plane m 3 conrotatory bsh1on.