Current Computer - Aided Drug Design - Volume 8, Issue 2, 2012

It is with great pleasure, a sense of honor, and humility that we took up the responsibility of editing a special issue of Current Computer-Aided Drug Design (CCADD) dedicated to Professor Lemont B. Kier to celebrate his eightieth birthday. One of us (Basak) has been using some of Professor Kier’s concepts and methods since the 1970s, when he started his research on the use of mathematical structural descriptors in the characterization of molecular structure and quantitative structure-activity relationships (QSARs) of bioactive chemicals. Professor Kier continues to have an illustrious scientific career spanning over five decades (1958- till date) working on a diversity of areas including experimental and theoretical aspects of drug research and pharmacology. In the realm of computer-aided drug design, chemoinformatics, and bioinformatics, his seminal contributions have been principally in three areas: a) Use of molecular orbital theory in drug research, 2) Applications of molecular topology in QSAR, and 3) Characterization of biological complexity. He has mentored a large number of graduate students and postdocs as well as collaborated with many visiting fellows from the United States and around the world. Monty, as friends are used to call him affectionately, has published over 280 research papers, authored seven books; received grants, contracts and consultancy invitations from numerous government agencies and multinational companies, has been a member of many scientific organizations in the field of drug research, and has been on the editorial boards of numerous journals in his field, including CCADD. The above summary undoubtedly indicates a long and outstanding scientific career. The wide impact of his research is reflected in the more than 11,000 citations of his publications up to the end of February, 2012. We invited our colleagues working in the area of computer-aided drug design to contribute to the special issue of CCADD honoring Monty. A large number of contributors came forward from around the globe. We will need more than one issue of the journal to accommodate all the contributions. This issue contains the first batch of papers published in Monty’s honor. In the first article, Bernard Testa pays tribute to Professor Kier and gives a brief summary of the long lasting collaboration he has had with him in drug research going back to 1990.....

To pay tribute to Lemont B. Kier in this special issue of CCADD is an honor and a joy. Monty and I have been associated for many years, but his influence on my scientific life began well before we met. The year was 1970, and my mind was occupied with two major projects, writing up my PhD thesis and finding a suitable institution abroad for post-doctoral studies. At that time, I saw -- and immediately bought -- a book edited by L.B.K and entitled “Molecular Orbital Theory in Chemical Pharmacology: A Symposium held at Battelle Seattle Research Center”. This book, together with seminal works in stereochemistry and SAR, brought me for two years to the (now closed) Chelsea College of Science and Technology, University of London, where I was fortunate to learn my future trade under the inspiring and dedicated guidance of the late Prof. Arnold H. Beckett. It was there, on September 26, 1972, that I saw Monty for the first time. He had been invited by the Society for Drug Research to visit Chelsea College and give a formal lecture on “Conformation and drug action”. The large lecture hall was packed and left me no chance to interact with Monty, but the impression he made was indelible. Our first face-to-face meeting had to wait for another 16 years to occur. Indeed, Monty was one of the distinguished speakers at the 7th European QSAR Symposium chaired by my late and dear friend Jean-Luc Fauchere and held in Interlaken (Switzerland) in September 1988. Remarkably, a highlight of this Symposium was the celebration of the 70th birthday of Corwin Hansch. During this Symposium, I had long discussions with Monty and I even recall an outing with him and his wife Martha along the shore of the lake of Brienz. After the Symposium, they came to visit us in Lausanne - and this is where and when our long collaboration began. At that time, Monty's research interests had shifted toward electrotopological indices and were beginning to extend into physicochemical simulations using cellular automata. The latter area of research, together with musings on complexity, clinched our collaboration. During the 1989-2003 period, Monty spent eleven summers as a visiting scientist in our Institute of medicinal chemistry, totaling twenty-five months of presence! Of special note is his election in 1992 to the Chair of Honor of the University of Lausanne, indeed a very rare recognition. During his stays, Monty was busy carrying out his own research, but he was also most generous with his time, advising graduate students, giving numerous seminars and collaborating with the undersigned. The visible fruit of his collaboration was the joint publication of sixteen research papers and seven reviews, a selection of which appears at the end of this text. For more than five decades now, Monty has been a pioneer in computational studies. His earlier work on conformational factors in structure-activity relationships supplied the missing stepping-stone toward a realistic three-dimensional understanding of pharmacophores. His subsequent creation and development of electrotopological indices allowed fast encoding of stereoelectronic features and in silico high-throughput screening of chemical libraries. Cellular automata simulations, his last pet topic, have been less practical in the questions they addressed. Their main value, in my view, is the didactic and inspiring insights they allow. Each of these three fields would have filled the career of a gifted medicinal chemist. But Monty is more than a gifted scientist - he is a discoverer and leader. The worldwide community of medicinal chemists owes much to him, as this timely special issue of CCADD testifies. SELECTED PAPERS [1] Fan, W.; El Tayar, N.; Testa, B.; Kier, L.B. Water-dragging effect: a new experimental hydration parameter related to hydrogen-bond donor acidity. J. Phys. Chem., 1990, 94, 4764-4766. [2] Testa, B.; Kier, L.B. The concept of molecular structure in structure-activity relationship studies and drug design. Med. Res. Rev., 1991, 11, 35-48. [3] Tsai, R.S.; Fan, W.; El Tayar, N.; Carrupt, P.A.; Testa, B.; Kier, L.B. Solute-water interactions in the organic phase of a biphasic system. I. Structural influence of organic solutes on the “water-dragging” effect. J. Am. Chem. Soc., 1993, 115, 9632-9639. [4] Kier, L.B.; Cheng, C.K.; Testa, B.; Carrupt, P.A. A cellular automata model of the hydrophobic effect. Pharm. Res., 1995, 12, 615-620. [5] Kier, L.B.; Cheng, C.K.; Testa, B.; Carrupt, P.A. A cellular automata model of micelle formation. Pharm. Res., 1996, 13, 1419-1422. [6] Kier, L.B.; Cheng, C.K.; Testa, B.; Carrupt, P.A. A cellular automata model of enzyme kinetics. J. Molec. Graphics, 1996, 14, 227-231. [7] Testa, B.; Kier, L.B.; Carrupt, P.A. A systems approach to molecular structure, intermolecular recognition, and emergence-dissolvence in medicinal research. Med. Res. Rev., 1997, 17, 303-326. [8] Kier, L.B.; Cheng, C.K.; Testa, B.; Carrupt, P.A. A cellular automata model of aqueous diffusion. J. Pharm. Sci., 1997, 86, 774-778. [9] Kier, L.B.; Cheng, C.K.; Testa, B. A cellular automata model of the percolation process. J. Chem. Inform. Comput. Sci., 1999, 39, 326-332. [10] Testa, B.; Raynaud, I.; Kier, L.B. What differenciates free amino acids and amino acyl residues ? An exploration of conformational and lipophilicity spaces. Helv. Chim. Acta, 1999, 82, 657-665. [11] Kier, L.B.; Cheng, C.K.; Testa, B. Cellular automata models of biochemical phenomena. J. Future Generation Computer Systems, 1999, 16, 273-289. [12] Testa, B.; Kier, L.B. Emergence and dissolvence in the self-organization of complex systems. Entropy, 2000, 2, 1-25. *Free access: http://www.mdpi.net/entropy/papers/e2010001.pdf [13] Testa, B.; Kier, L.B.; Cheng, C.K. A cellular automata model of water structuring by a chiral solute. J. Chem. Inform. Comput. Sci., 2002, 42, 712-716. [14] Kier, L.B.; Cheng, C.K.; Testa, B. A cellular automata model of ligand passage over a protein hydrodynamic landscape. J. Theor. Biol., 2002, 215, 415-426. [15] Kier, L.B.; Cheng, C.K.; Testa, B. Studies of ligand diffusion pathways over a protein surface. J. Chem. Inform. Comput. Sci., 2003, 43, 255-258.

Models of water in the presence of amino acid side chains have revealed significant variability in the local water structure, reflecting the variations in the hydropathic states of the side chains. These models also reveal patterns of water cavities, termed chreodes, that may exist near the surface of a protein. These patterns have been invoked to explain the facilitated diffusion of ligands to an active site on the protein surface. The action of a volatile, general anesthetic agent has been proposed to occur from the interruption of these chreodes producing some loss of function from the receptor. The many similarities reported between the effects of a general anesthetic agent and sleep have produced a proposal of a common mechanism. In the case of sleep, it has been proposed that inhaled elemental nitrogen accumulates to produce a mild anesthesia. Sleep is the process of reversal of this accumulation. It is proposed that over a lifetime there is a continued accumulation of nitrogen with accompanying influences on many processes, leading to a gradual decline of many functions, called aging. The sequence of these concepts is reviewed here.

This review is a salute to Monty Kier’s creativity. Emphasis is placed on creative aspects in the development of the representation of molecular topological structure information and the resultant formalisms: molecular connectivity and electrotopological state (E-State). Less attention is given to detailed analysis of individual papers and the generally well known books and book chapters. This discussion reveals creative paths that led to the concept of the atomic descriptors, simple connectivity delta, encoding local topology, and valence delta value which encodes valence electron information. The fundamental developments that led to the creation of molecular connectivity chi indices are described along with extensions to different chi and delta chi formalisms. Continued thinking about structure in the topological sense led to the development of the only valence state electronegativity formalism based entirely on structure, Kier-Hall electronegativity (KHE). That creation further inspired the development of the electronegativity/topology-based atomic intrinsic state along with perturbation terms that together give electrotopological state indices (E-State). Further creation led to atom and bond type E-State descriptors. All these developments are briefly illustrated with examples in QSAR, chemical similarity, and database searching.

Carefully developed quantitative structure-activity and structure-property relationship models contain detailed information regarding how differences in the molecular structure of compounds correlate with differences in the observed biological or other physicochemical properties of those compounds. The ability to understand the behavior of existing molecules and to design new molecules is facilitated by using an objective method to extract and explain the details of the underlying structure-activity or structure-property relationship. Furthermore, a clear understanding of how and why compounds behave as they do can lead to new innovations through model-directed selection of compounds to be used in complex mixtures such as laundry detergents, fabric softeners, and shampoos. Such a method has been developed based on partial least-squares (PLS) regression analysis that allows for the identification of specific structural trends that relate to differences in observed properties. But the analysis of the completed model is only the last step of the process. The model development process itself affects the ability to extract a clear interpretation of the model. Everything from the selection of initial pool of molecular descriptors to evaluate to data set and model optimization impacts the ability to derive detailed molecular design information. This review describes the method details and examples of the use of PLS for model interpretation and also outlines suggestions regarding model development and model and data set optimization that enable the interpretation process.

The last few decades have witnessed application of graph theory and topological indices derived from molecular graph in structure-activity analysis. Such applications are based on regression and various multivariate analyses. Most of the topological indices are computed for the whole molecule and used as descriptors for explaining properties/activities of chemical compounds. However, some substructural descriptors in the form of topological distance based vertex indices have been found to be useful in identifying activity related substructures and in predicting pharmacological and toxicological activities of bioactive compounds. Another important aspect of drug discovery e.g. designing novel pharmaceutical candidates could also be done from the distance distribution associated with such vertex indices. In this article, we will review the development and applications of this approach both in activity prediction as well as in designing novel compounds.

Over the last two decades, a great deal of research has been oriented towards determination of correlation between molecular structures and a variety of responses exhibited by such molecules. Extensive attempts have been made to quantitatively determine the influence of structural fragments on the property profile of molecules through the development of quantitative structure-activity/property/toxicity relationship (QSAR/QSPR/QSTR) models based on regression analysis using different descriptors. Among all descriptors, the topological ones constitute an essential class encoding the crucial structural fragments governing the activity/property or toxicity data of the molecules. To better indicate the important topological features and molecular fragments mediating a particular response, Kier and Hall developed the electrotopological state atom (E-state) indices in the early 90s. The ability to encode the topology and electronic environment of molecular fragments in unison portrayed the E-state indices as an indispensable tool in the field of QSAR/QSPR/QSTR studies. This review looks back at different applications of E-state indices in the field of quantitative analysis of molecular properties as a function of their structures for diverse groups of molecules with vivid range of response parameters. The studies summarized here would help to understand potential of the E-state indices to identify the structural attributes responsible for various responses of the molecules. Although the present review includes most of the important researches carried out employing E-state parameters as the major group of descriptors over the last 15 years, the search is not exhaustive one. Apart from the studies reviewed here, several other researches have also been performed where the E-state indices have been engaged in association with several other descriptors to determine the influential molecular fragments for various endpoints.

An important area of theoretical drug design research is quantitative structure activity relationship (QSAR) using structural invariants. The impetus for this research trend comes from various directions. Researchers in chemical documentation have searched for a set of invariants which will be more convenient than the adjacency matrix (or connection table) for the storage and comparison of chemical structures [1]. Molecular structure can be looked upon as the representation of the relationship among its various constituents. The term molecular structure represents a set of nonequivalent and probably disjoint concepts [2]. There is no reason to believe that when we discuss diverse topics (e.g. chemical synthesis, reaction rates, spectroscopic transitions, reaction mechanisms, and ab initio calculations) using the notion of molecular structure, the different meanings we attach to the single term molecular structure originate from the same fundamental concept. On the contrary, there is a theoretical and philosophical basis for the non-homogeneity of concepts covered by the term molecular structure. In the context of molecular science, the various concepts of molecular structure (e.g. classical valence bond representations, various chemical graph-theoretic representations, ball and spoke model of a molecule, representation of a molecule by minimum energy conformation, semi symbolic contour map of a molecule, or symbolic representation of chemical species by Hamiltonian operators) are model objects [3] derived through different abstractions of the same chemical reality. In each instance, the equivalence class (concept or model of molecular structure) is generated by selecting certain aspects while ignoring some unique properties of those actual events. This explains the plurality of the concept of molecular structure and their autonomous nature, the word autonomous being used in the same sense that one concept is not logically derived from the other. At the most fundamental level, the structural model of an assembled entity (e.g. a molecule consisting of atoms) may be defined as the pattern of relationship among its parts as distinct from the values associated with them [4]. Constitutional formulae of molecules are graphs where vertices represent the set of atoms and edges represent chemical bonds [5]. The pattern of connectedness of atoms in a molecule is preserved by constitutional graphs. A graph (more correctly a non-directed graph) G = [V, E] consists of a finite non-empty set V of points together with a prescribed set E of unordered pairs of distinct points of V [6]. Thus the mathematical characterization of structures represents structural invariants having successful applications in chemical documentation, characterization of molecular branching, enumeration of molecular constitutional associated with a particular empirical formula, calculation of quantum chemical parameters for the generation of quantitative structure-property-activity correlations [7]. Kier developed a number of structural invariants which are now-a-days called as topological indices with wide range of practical applications for QSAR and drug design. The present paper is restricted to the review of Kier-Hall topological indices for QSAR and anticancer drug design for 2,5-bis(1-aziridinyl) 1,4-benzoquinone (BABQ) [8], pyridopyrimidine [9], 4-anilinoquinazoline [10] and 2-Phenylindoles [11] compounds utilizing various statistical multivariate regression analyses.