Minimum topological difference approach

Balaban et al. (7 ) recently published a method which partly overcomes the above-mentioned problems. This MTD (minimum topological difference) approach is trying to develop an optimal standard molecule by systematically analyzing the shapes of the members in a series in relation to their biological activities. 

The Minimum Topological Difference (MTD) approach developed by Z. Simon and T. Oprea, especially in its newer MTD-PLS variant employing the PLS regression analysis, successfully relates the activity to the presence and physicochemical parameters of the atoms and fragments defined over a quasi-3D hypermolecule as well as global physicochemical descriptors. Despite some methodological problems and limitations, this approach is promising and in active current development. ... 

In another approach, with an aim to offer a realistic motive towards handling millions of databases and hundreds of descriptors for a fruitful structure-activity relationship (SAR), Putz and coworkers have proposed a unique QSAR model called spectral-SAR (S-SAR) [220], which considers the spectral norm in quantifying toxicity and reactivity with molecular structure. A handful of applications of the S-SAR algorithm in dealing with ecotoxicity, enzyme activity, and anticancer bioactivity are well established [221-227]. The S-SAR model coupled with Element Specific Influence Parameter (ESIP) formulations [228] are also utilized for predicting ecotoxicity measures. QSAR studies on the anti-HIV-1 activity of HEPT (l-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine) [229] and further studies involving the minimum topological difference (MTD) method [230, 231] are also reported [232]. 

Finally, an alchemical free energy simulation is needed to obtain the free energy difference between any one substate of system A and any one substate of system B, e.g., Ai- In practice, one chooses two substates that resemble each other as much as possible. In the alchemical simulation, it is necessary to restrain appropriate parts of the system to remain in the chosen substate. Thus, for the present hybrid Asp/Asn molecule, the Asp side chain should be confined to the Asp substate I and the Asn side chain confined to its substate I. Flat-bottomed dihedral restraints can achieve this very conveniently [38], in such a way that the most populated configurations (near the energy minimum) are hardly perturbed by the restraints. Note that if the substates AI and BI differ substantially, the transfomnation will be difficult to perform with a single-topology approach. 

As explained above, despite the fact that the interactions do not depend on the concentration, the diffuse intensity maps of Ala V and AtgC are very different. This behavior is in total contradiction with a mean field approach According to the Krivoglaz-Clapp-Moss formula", a minimum of V (c/) corresponds of a maximum of mean field approach cannot explain the topology changes observed in the diffuse intensity maps. 

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