Molecular modeling approach

A. M. ter laak, N. P. E. Vermeulen, Molecular-modeling approaches to predict metabolism and toxicity, in Pharmacokinetic Optimization in Drug Research, B. Testa, H. van de Water-beemd, G. Folkers, R. Guy (Eds.), Wiley-VCH, Weinheim, 2001,... 

The molecular modelling approach, taking into account the pyruvate—cinchona alkaloid interaction and the steric constraints imposed by the adsorption on the platinum surface, leads to a reasonable explanation for the enantio-differentiation of this system. Although the prediction of the complex formed between the methyl pyruvate and the cinchona modifiers have been made for an ideal case (solvent effects and a quantum description of the interaction with the platinum surface atoms were not considered), this approach proved to be very helpful in the search of new modifiers. The search strategy, which included a systematic reduction of the cinchona alkaloid structure to the essential functional parts and validation of the steric constraints imposed to the interaction complex between modifier and methyl pyruvate by means of molecular modelling, indicated that simple chiral aminoalcohols should be promising substitutes for cinchona alkaloid modifiers. Using the Sharpless symmetric dihydroxylation as a key step, a series of enantiomerically pure 2-hydroxy-2-aryl-ethylamines... 

Paluchowska et al. (2002) reported the synthesis, pharmacological studies, and conformational analysis utilizing classical molecular modeling approaches of some arylpiperazine or 1,2,3,4-tetrahydroisoquinoline derivatives of the known and flexible 5-HT ia receptor ligands with different intrinsic activities at nanomolar levels [63]. The SAR is shown in Table 4. The synthetic steps involved for some of the compounds mentioned in Table 4 are shown in Scheme 2 [63]. 

As discussed in Section 6.5.3, coarse-grained molecular modeling approaches offer the most viable route to the molecular modeling of hydrated ionomer membranes. The coarse-grained treatment implies simplification in interactions, which can be systematically improved with advanced forcematching procedures, but allows simulations of systems with sufficient size and sufficient statistical sampling. Structural correlations, thermodynamic properties, and transport parameters can be studied. 

Robust peptide-derived approaches aim to identify a small drug-like molecule to mimic the peptide interactions. The primary peptide molecule is considered in these approaches as a tool compound to demonstrate that small molecules can compete with a given interaction. A variety of chemical, 3D structural and molecular modeling approaches are used to validate the essential 3D pharmacophore model which in turn is the basis for the design of the mimics. The chemical approaches include in addition to N- and C-terminal truncations a variety of positional scanning methods. Using alanine scans one can identify the key pharmacophore points D-amino-acid or proline scans allow stabilization of (i-turn structures cyclic scans bias the peptide or portions of the peptide in a particular conformation (a-helix, (i-turn and so on) other scans, like N-methyl-amino-acid scans and amide-bond-replacement (depsi-peptides) scans aim to improve the ADME properties." ... 

Interestingly, the undifferentiated antibacterial activity against both methicillin-susceptible and -resistant strains of Staphylococcus aureus was suggestive of an alternative mechanism of action compared to that of typical (3-lactams. The molecular modeling approach allowed the identification of interactions through oxygenated functions such as phenolic OH, which are valuable for the antibacterial activity [294]. 

In the remainder of this chapter, newly developed methods such as a molecular modeling approach (Bodor and Huang, 1992 Zhou et al., 1993), a group contribution approach (V Mita et al., 1986 Klopman et al., 1992 Kthne et al., 1995 Myrdal et al., 1995), and a frequently used linear free-energy relationship method (Taft et al., 1985 Lee, 1996) will be discussed. 

Equation 3.47 shows that the predicted results are remarkably close to the experimental values, since the slope in near unity and the intercept are essentially negligible. Once again, a molecular modeling approach is promising for predicting the solubility of different classes of compounds. 

Zhou, H., R. Liu, Y. Chen, and L. E. Matheson. 1993. A 3-dimensional molecular modeling approach for prediction of aqueous solubilities of aromatic compouiRtaarm. Res10 S261. 

It is worth noticing that a molecular modelling approach is used to complement the experimental techniques of dynamic mechanical analysis, dielectric relaxation, solid-state 13C and 2H NMR. 

A molecular modelling approach to the ester group of MMA units, using the quasi-static dynamics, as already described for PMMA (Sect. 8.1.5) and CMIM20 (Sect. 8.2.4), has been applied to MGIMx copolymers [78]. 

Studies of the ability of the lipase B from Candida antarctica (CAL-B) to catalyse the enantioselective aminolysis of esters by cis- and firms-2-phenylcycloalkanamines (54 n = 1, 3, 4) have been followed up by molecular modelling approaches in order to probe the lipase-catalysed aminolysis mechanism. CAL-B possesses a typical serine-dependent triad, so it was possible, with access to an X-ray crystal structure of CAL-B, to model a series of phosphonamidates (55 n = 1, 3, 4) as analogues of the tetrahedral intermediate (TI) resulting from attack of the amine on the carbonyl of the acyl-enzyme. The results suggested as the most plausible intermediate for the CAL-B-catalysed aminolysis a zwitterionic TI resulting from the direct His-assisted attack of the amine on to a C=0 group of the acyl-enzyme.80... 

Iyer SS, Zhang ZP, Kellogg GE, Karnes HT (2004) Evaluation of deuterium isotope effects in normal-phase LC-MS-MS separations using a molecular modeling approach. J Chromatogr Sd 42 383-387... 

Molecular Modeling Approaches to Study the Binding Mode on Tubulin of Microtubule Destabilizing and Stabilizing Agents... 

Molecular Modeling Approaches to Study the Binding Mode... 

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