You are hereA REVIEW ON ROLE OF MOLECULAR DESCRIPTORS IN QSAR: A COMPUTATIONAL METHODS APPROACH
A REVIEW ON ROLE OF MOLECULAR DESCRIPTORS IN QSAR: A COMPUTATIONAL METHODS APPROACH
5. DESCRIPTOR SELECTION:
To build agood QSAR model, a minimal set of information-rich descriptors is required. The large number of possible indices creates several problems for the modeler [57, 58].
1. Many descriptors do not contain molecular information relevant to the problem.
2. Many descriptors are linearly dependant (contain essentially the same information).
3. Use of poor descriptors in QSAR yields poor and misleading models.
4. Including too many descriptors in the model, even if they contain relevant information, can result in over fitting of the model, and loss of ability of the model to generalize to unseen molecules.
5. Many methods of screening this large pool of potential descriptors for relevant ones can lead to chance correlations (correlations that arise by chance because so many descriptors have been tried in models). In other words, if many random numbers are generated as potential descriptors (which clearly do not contain any useful molecular information), and various subsets of these are used to build models, apparently significant models can arise by chance.
The earliest method of variable selection used stepwise regression. This was integrated with the model-building process and involved stepwise addition (or backwards elimination) of descriptors according to a statistical test, to find the best model. Another widely used variable reduction method is principle components analysis (PCA). This involves creating a smaller set of new orthogonal descriptors from linear combinations of the original descriptors and using these to generate QSAR models.
The 2D- Versus 3D-QSAR Approach
Studies show that assumption of superiorness of 3D approaches to 2D in drug design may not always hold. For example, the results of conventional CoMFA may often be non-reproducible due to dependence of the outputs' quality on the orientation of the rigidly aligned molecules on user's terminal [59, 60]. Such alignment problems are typical in 3D approaches and even though some solutions have been proposed, the unambiguous 3D alignment of structurally diverse molecules remains a difficult task. Moreover, the distinction between 2D- and 3D-QSAR approaches is not a crisp one, especially when alignment independent descriptors are considered. This can be observed when comparing the BCUT with the WHIM descriptors. Both employ a similar algebraic method, i.e., solving an Eigen problem for a matrix describing the compound the connectivity matrix in case of BCUT descriptors and covariance matrix of 3D co-ordinates in case of WHIM. There is also a deeper connection between 3D-QSAR and one of 2D methods, the topological approach. It stems from the fact that the geometry of a compound often depends on its topology. An elegant example was provided by Estrada et al., who demonstrated that the dihedral angles of biphenyl as a function of the substituents attached to it can be predicted by topological indices . Along the same line, a supposedly typically 3D property, chirality, has been predicted using chiral topological indices , constructed by introducing an adequate weight into the topological matrix for the chiral carbons.
We have discussed traditional QSAR, now termed 2D-QSAR and 3D-QSAR. The QSAR relations were determined using logic about important parameters and had to rely on statistical correlations of structural descriptors with biological activities. There were some significant limitations with using the QSAR relations developed to predict better drugs. Today, 3D-QSAR uses model computational methods and technologies such as statistical correlation, machine learning, and 3D visualization, yielding rational for computer assisted drug design. There are software products that enable the design and construction of the QSAR models in an optimal fashion.
QSAR has been applied extensively and successfully over several decades to find predictive models for activity of bioactive agents. It has also been applied to areas related to discovery and subsequent development of bioactive agents: distinguishing drug-like from non-drug like molecules , drug resistance , toxicity prediction [65-70], physicochemical properties prediction (e.g. water solubility, lipophilicity) , gastrointestinal absorption , activity of peptides , data mining , drug metabolism  and prediction of other pharmacokinetic and ADME properties [76, 77]. Clearly the number of potential applications for structure-property modeling, in the most general case, is extensive and growing daily. Improved molecular descriptors, based on a better understanding of which molecular attributes are most important for a given property being modeled, and increasing use of genetic and artificial intelligence methods will raise QSAR to even greater levels of usefulness than the current high level.
Despite of several limitations, it has a now been globally apprehended by the contemporary drug discovery community that QSAR, based on well-established principals of statistics, is intrinsically a valuable and viable medicinal chemistry tool whose application domain range from explaining the structure-activity relationships quantitatively and retrospectively, to endowing synthetic guidance leading to logical and experimentally testable hypotheses. The development of QSARs in last 40 years has evolved both in terms of descriptor generation and data analysis. It involves the mathematical and statistical analysis of SAR-data which helps to reduce the number of educated guesses in molecular modification.QSAR is thus a scientific achievement and an economic necessity to reduce empiricism in drug design to ensure that every drug synthesized and pharmacologically tested should be as meaningful. A basic understanding of QSAR concepts is essential for most people, across a diverse range of skills.
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