We recently reported that the information about

We recently reported that the information about the electronic density obtained from a QTAIM analysis is useful to describe the molecular interactions that stabilize and destabilize the different complexes L-R [13], [14], [15]. Specifically in our previous work reported for DHFR inhibitors, the QTAIM analysis gave very interesting results when it was applied to this molecular target [5]. Therefore in the next stage of our study we performed a QTAIM analysis of all the complexes in order to find a new descriptor for this series.
Conclusions In this paper we have succeeded in what we fail in our previous report [5]. In this case we have been able to get an excellent correlation between the electronic densities obtained from a QTAIM study with the experimental data. It is important to note that through this study is possible to differentiate the L-R affinity even though the compounds possess similar affinities. Very important additional information obtained through this type of study is that it is possible to visualize which mt t are involved in the interactions determining the different affinities of the ligands. Such information is crucial when we are interested in the design of new specific ligands. Some additional benefits that may be mentioned for this approach are: the technique is relatively simple, easy to interpret and not too demanding about the computing time. However, a somewhat limiting aspect of this type of study is that the QTAIM study is highly dependent on the optimized geometry and therefore the conformational variability can be a serious problem. In the particular case of DHFR this is not too problematic due to the structural characteristics of the active site of the enzyme. It is well known that the DHFR binding pocket is relatively narrow, with little space for the ligand and therefore does not lead to large conformational changes at least in comparison with others more flexible binding sites. These features of the active site have allowed that with care in the calculations (four conformations for each complex were considered), it is possible to obtain highly satisfactory results. Clearly, if the characteristics of the active site are different it is necessary to check whether this technique is effective exactly with this procedure or if it is necessary to consider more carefully the issue of conformational variability of the various complexes.
Acknowledgments Grants from Universidad Nacional de San Luis (UNSL), partially supported this work. This research was also supported by the Spanish “Ministerio de Educación y Ciencia” grant SAF 2007-63142. Rodrigo Tosso thanks a doctoral fellowship of CONICET-Argentina. R. D. Enriz and S. A. Andujar are members of the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET-Argentina) staff. We especially acknowledge MSc. Daniel O. Zamo for technical assistance.
Introduction High throughput screening (HTS) exercises are now become an integral part of any drug discovery project. This screening exercise heavily depends on the rapid and efficient supply of novel scaffolds and chemotypes (Congreve et al., 2005, Crews, 2010, Ghosh et al., 2006, Mayr and Bojanic, 2009). Owing to suitability for automation and miniaturization, certain reaction classes such as multicomponent (MCRs)/click along with others, find important place in combinatorial chemistry, library design and HTS and are quite relevant in drug discovery projects (Teague et al., 1999, Bienaymé et al., 2000). The fast delivery of novel chemical entities (NCEs) alone does not guarantee success in any drug discovery project. One factor that should also be taken into account is that optimization from hit to lead and then to drug is a very time consuming and expensive process with high attrition rate (Bleicher et al., 2003). As a result, only very limited academic set ups (especially funded by industry) can manage this huge financial burden. Considering this uncertainty, prioritization of available chemical resources seems very crucial for any medicinal chemist.