Molecular library design

Molecular Library Design Using Multi-Objective Optimization Methods... 

Key words Multi-objective molecular library design, multi-objective evolutionary algorithm,... 

Problems that require the accommodation of multiple objectives, such as molecular library design, are widely known as multiobjective problems (MOP) or vector optimization problems... 

Multi-objective Molecular Library Design Applications... 

R.A. Lewis, S.D. Pickett, D.E. Qark. Computer-aided molecular diversity analysis and combinatorial library design, in Reviews in Computational Chemistry, Vol. 16, K.B. Opkowitz, D.B. Boyd (Eds.). Wiley-VCH, New York. 2000. pp. 8-51. 

Several research groups have built models using theoretical desaiptors calculated only from the molecular structure. This approach has been proven to be particularly successful for the prediction of solubility without the need for descriptors of experimental data. Thus, it is also suitable for virtual data screening and library design. The descriptors include 2D (two-dimensional, or topological) descriptors, and 3D (three-dimensional, or geometric) descriptors, as well as electronic descriptors. 

D descriptors are simple and easy to imderstand, while the 3D descriptors contain more information. The descriptors of both methods were derived from the molecular structures. Thus the models that were developed here are suitable for in-sdico data screening and library design. 

In general, the described techniques provide an effective, flexible, and relatively fast solution for library design based on analysis of bioscreening data. The quantitative relationships, based on the assessment of contribution values of various molecular descriptors, not only permit the estimation of potential biological activity of candidate compounds before synthesis but also provide information concerning the modification of the structural features necessary for this activity. Usually these techniques are applied in the form of computational filters for constraining the size of virtual combinatorial libraries and... 

Knowledge-based data mining algorithms used for correlation of molecular properties with specific activities play an increasingly significant role in modern strategies of chemical library design as relatively inexpensive, yet comprehensive tools. The ability to identify compounds with the desired... 

The genesis of in silico oral bioavailability predictions can be traced back to Lip-inski s Rule of Five and others qualitative attempts to describe drug-like molecules [13-15]. These processes are useful primarily as a qualitative tool in the early stage library design and in the candidate selection. Despite its large number of falsepositive results, Lipinski s Rule of Five has come into wide use as a qualitative tool to help the chemist design bioavailable compounds. It was concluded that compounds are most likely to have poor absorption when the molecular weight is >500, the calculated octan-l-ol/water partition coefficient (c log P) is >5, the number of H-bond donors is >5, and the number of H-bond acceptors is >10. Computation of these properties is now available as an ADME (absorption, distribution, metabolism, excretion) screen in commercial software such as Tsar (from Accelrys). The rule-of-5 should be seen as a qualitative, rather than quantitative, predictor of absorption and permeability [16, 17]. 

Richard A. Lewis, Stephen D. Pickett, and David E. Clark, Computer-Aided Molecular Diversity Analysis and Combinatorial Library Design. 

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