Drug Design 2 - Applied Bioinformatics Group

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0D Descriptors • The simplest descriptors count trivial proper%es of the structure • Molecular weight (MW) • Number of atoms • Number of carbon atoms • Number of heavy atoms • Number of bonds • Number of 3-‐/4-‐/5-‐/6-‐membered rings • Number of aroma%c rings • .... • Although simple, these descriptors are very powerful and part of many QSPR models (MW, for examples, is essen%al for bioavailability!) • Advantages • Easy to compute • Disadvantages • No informa%on on topology, geometry, ... 1D Descriptors • These descriptors correspond to structural fingerprints • They count the number of certain fragments or atom types • Number of sp 3 carbons • Number of each of the Ghose&Crippen atom types • Number of hydroxyl groups • Number of H-‐bond donors • Number of amino groups • ... • These descriptors capture some key chemical features of the structure • They are sufficient to predict some key proper%es based on increment models (AlogP is an example for this) 2D Descriptors • 2D descriptors account for topological properDes • They are derived from the molecular graph of the structure • They encode informa%on on • Size • Branching • Shape (topological, not geometrical!) • ... of the structures • They are more expensive to compute than 1D descriptors, but s%ll rather cheap
Wiener Index • In 1947, H. Wiener observed that the boiling point of alkanes can be predicted based on their topology • For n-‐alkanes this is trivial based on chain length alone, but not for branched alkanes • For example, different nonanes have boiling points between 122°C (2,2,4,4-‐tetramethyl-‐ pentane) and 150°C (n-‐nonane) • Wiener proposed to model the boiling point as a linear funcDon of two variables, p and w: T B = a p + b w + c with constants a, b, c • Based on this simple model, he could predict boiling points with an accuracy of about 1 K Wiener Index • p is called polarity number, a 1D descriptor, coun%ng the number of carbon-‐carbon pairs separated by exactly three bonds (C—C—C—C) • W, the path number, is a topological descriptor and is also called Wiener index • w is the sum of lengths of all pairwise paths in the molecular graph • In acyclic alkanes this corresponds to the product of all atoms to the lem and to the right of any bond Wiener Index T B / °C 250 200 150 100 50 0 4 6 8 Chain Kettenlänge length 10 12 Boiling points of n-alkanes 3 1 2 4 5 D 1,2 = 1, D 3,5 = 3, ... w = (1·4) + (4·1) + (3·2) + (4·1) = 18 • There is a large number of generaliza%ons of the Wiener index to make it applicable for cyclic structures as well • A widely used defini%on is half the sum of the entries of the distance matrix of the molecular graph (= sum of all minimal pair-‐ wise paths) • Wiener index is omen used if the degree of branchedness is relevant for a property • It is also relevant for predic%ng pharmacological ac%vi%es, e.g., there are models for carboanhydrase II inhibitor ac%vity based on the Wiener index 4 4 6 4 Saxena, Khadikar, Acta Pharm. 49 (1999) 171-179
Page 1 and 2: Number of Candidates Overview BIOIN
Page 3 and 4: Reduce AZriDon Rate • „Fail ear
Page 5 and 6: log P and log k • Biological barr
Page 7 and 8: Enteral AbsorpDon Neutral compound
Page 9 and 10: ClogP • ClogP now adds the contri
Page 11: QSPR • Representa%on of a structu
Page 15 and 16: Topological Indices • There is a
Page 17 and 18: 3D Descriptors - PSA • A very pop
Page 19 and 20: Drug-‐Likeness • Sadowski et
Page 21 and 22: Drug-‐Likeness • Ajay et al.

Drug Design 2 - Applied Bioinformatics Group

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