SAR/SPR

A lead is variously defined in the pharmaceutical industry as a compound derived from a hit with some degree of in vitro optimization (potency in primary assay, activity in functional and/or cellular assay), optimization of physical properties (solubility, permeability), and optimization of in vitro ADME properties (microsomal stability, CYP inhibition). Moreover, a lead must have established SAR/SPR around these parameters such that continued optimization appears possible. A lead may also have preliminary PK and in vivo animal model data. However, it is the task of the lead optimization chemist to improve PK and in vivo activity to the levels needed for identification of a clinical candidate. 

SAR (Structure Activity Relationships)/SPR (Structure Property Relationships) for eye irritation and skin corrosion are shown separately but in reality would probably be done in parallel. This stage should be completed using validated and accepted SAR/SPR approaches. The SAR/SPR analysis may identify serious eye damage, corrosion and irritation potential for both skin and eye effects ... 

In summary, we hope that the examples in this chapter could show the broad range of topics a Cl researcher is confronted with in an industrial environment. There is a variety of ways how Cl can contribute significantly to pharmaceutical research projects. Cl remains an interesting area with a number of open challenges to be solved, limited understanding of SAR/SPR in all of its complexities being only one of them. 

Recent day, quantum mechanics becomes very popular to explain the mechanistic features of bio-active molecules. There are several quantum chemical descriptors through which we can predict reaction mechanism and as well as stmcture activity relationship of munerous bioactive molecules. A number of excellent reviews have been pubhshed on the application of quantum chemical descriptors in SAR/SPR studies [24—26]. To determine the equilibrium geometry, the molecular force field and to compute the quantum mechanical descriptors of the dmg molecules, some suitable quantum mechanical method are invoked [27]. 

This is the domain of establishing Structure-Property or Structure-Activity Relationships (SPR or SAR), or even of finding such relationships in a quantitative manner (QSPR or QSAR). 

Building predictive QSAR and QSPR models is a cost-effective way to estimate biological activities, physicochemical properties such as partition coefficients and solubility, and more complicated pharmaceutical endpoints such as metabolic stability and volume of distribution. It seems to be reasonable to assume that structurally similar molecules should behave similarly. That is, similar molecules should have similar biological activities and physicochemical properties. This is the (Q)SAR/(Q)SPR hypothesis. Qualitatively, both molecular interactions and molecular properties are determined by, and therefore are functions of, molecular structures. Or... 

A tiered testing and evaluation scheme is presented that combines pre-existing information on serious ocular tissue damage and on eye irritation (including data relating to historical human or animal experience) as well as considerations on structure-activity relationships (SAR) or structure-property relationships (SPR) and the output of validated in vitro tests in order to avoid unnecessary animal testing. 

Compound quality is addressed with a rapid LC/UV/MS assay [12]. Many groups use compounds that were synthesized several years before or obtained from an outside source. Structure assignment inaccuracies, impurities, and degradants can cause SAR and SPR confusion for the drug-discovery team. 

Multivariate data analysis can be coupled with data visualization programs, such as Spotfire, to enhance data visualization [46]. Many of these visualization programs are currently being applied for HTS data to develop SAR and for data mining. Similar methodologies can also be used to visualize pharmaceutical-profiling data and for SPR. These visualization tools can be used interactively by medicinal chemists to help them look for the important interactions and provide conceptual understanding of structure-property relationships. 

TABLE 8. Some SPRS and SARS Based on Connectivity Indices... 

The molecular structure of any chemical will determine all of its physical, chemical and biological properties. Discovery chemists will therefore seek correlations between molecular structure and a desired property and the search for novel materials is therefore often guided by structure/ activity relationships (SARs). These can also be referred to as structure/ property relationships (SPRs) and when carried out with data inputs in a numerical form and using statistical methods for their analysis, the adjective quantitative is added giving quantitative structure/activity... 

TA-V installations that could potentially affect or be affected by the HCF include the Annular Core Research Reactor (ACRR), Gamma Irradiation Facility (GIF), Auxiliary Hot Cell Facility (AHCF), Radiation Metrology Laboratory (RML), and the Sandia Pulse Reactor III (SPR III). The GIF provides two cobalt cells for total dose irradiation environments. A new GIF is under construction in the northeast quadrant of TA-V. SPR III provides intense neutron bursts for effects testing of materials and electronics. The RML provides radiation measurement services to Sandia s reactors, isotopic sources, and accelerator facilities. The AHCF provides a capability to handle limited quantities of radioactive material in a shielded cell. These facilities have separate SARs that describe potential accidents. The most severe accidents for all of these facilities involve the release of radiological materials which could necessitate a site evacuation. No physical damage to the HCF could be induced by any of the postulated accidents, nor could any of the HCF accidents physically affect any of the other facilities. 

All these assays allow chemists, toxicologists, and biologists to obtain actionable information and provide a link between stracture-activity relationship (SAR) and structure-property relationship (SPR) that drive decisions on the selection of chemical series and molecules. 

Structure-activity relationship (SAR) and, more generally, stracture-property relationship (SPR) analysis are integral to the rational drag design cycle. Quantitative (QSAR, QSPR) methods assume that biological activity is correlated with chemical structures or properties and that as a consequence activity can be modelled as a function of calculable physiochemical attributes. Such a model for activity prediction could then be used, for instance, to screen candidate lead compounds or to suggest directions for new lead molecules. 

The most widely used types of topological indices are molecular connectivity indices. They have been widely reported as molecular structure descriptors in SPR studies and in structure-activity (SAR) studies as well. Originally developed by Randic/ and later modified by Kier and Hall, ° these indices have been used in a variety of studies. These indices are based on a graph theoretical treatment of the molecular topology of the compounds, and encode information about the branching and size of the molecules. The general equation for calculating molecular connectivities of the nth order is... 

Hence, stmctural information can be lost leading to similarity values of unity for pairs of molecules that are not stracturally identical. Nevertheless, there is at least a partial correspondence between the descriptors in the directory and the binary molecular FP of a molecule, so that it may be possible in many instances to associate particular substmctural features with molecular properties and/or biological activities, a characteristic that is not generally shared by molecule-dependent FP representations vide infra). This can be partially ameliorated through the use of weighted molecular FPs that take account of the nmnber of times a stractural feature occurs in a molecule. However, since not all structural features that may be associated with a specific structure-property relationship (SPR) or stmcture-activity relationship (S AR) are necessarily accounted for in given FP, it may not be possible to infer SPR or SAR even when weighted FPs are employed. 

Dragon Application for the calculation of molecular descriptors. Used to evaluate SAR or SPR, as well as for similarity analysis and HTS of molecule databases [50]... 

Soltani, S., Dianat, S., 8c Sardari, S. (2009). Forward modeling of the coumarin antifungals SPR/SAR based perspective avicenna. Journal of Medical... 

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