Employing conformational analysis in the molecular modeling of agrochemicals: insights on QSAR parameters of 2,4-D

Abstract

A common practice to compute ligand conformations of compounds with various degrees of freedom to be used in molecular modeling (QSAR and docking studies) is to perform a conformational distribution based on repeated random sampling, such as Monte-Carlo methods. Further calculations are often required. This short review describes some methods used for conformational analysis and the implications of using selected conformations in QSAR. A case study is developed for 2,4-dichlorophenoxyacetic acid (2,4-D), a widely used herbicide which binds to TIR1 ubiquitin ligase enzyme. The use of such an approach and semi-empirical calculations did not achieve all possible minima for 2,4-D. In addition, the conformations and respective energies obtained by the semi-empirical AM1 method do not match the calculated trends obtained by a high level DFT method. Similar findings were obtained for the carboxylate anion, which is the bioactive form. Finally, the crystal bioactive structure of 2,4-D was not found as a minimum when using Monte-Carlo/AM1 and is similarly populated with another conformer in implicit water solution according to optimization at the B3LYP/aug-cc-pVDZ level. Therefore, quantitative structure-activity relationship (QSAR) methods based on three dimensional chemical structures are not fundamental to provide predictive models for 2,4-D congeners as TIR1 ubiquitin ligase ligands, since they do not necessarily reflect the bioactive conformation of this molecule. This probably extends to other systems.Index terms: Structural analysis, 2,4-dichlorophenoxyacetic acid, theoretical calculations. RESUMOUma prática comum para determinar a conformação de ligantes em compostos com vários graus de liberdade a serem utilizados em modelagem molecular (QSAR e estudos de ancoramento molecular) é realizar uma distribuição conformacional baseada em repetidas amostragens aleatórias, tais como o método Monte Carlo. Cálculos adicionais são frequentemente necessários. Esta rápida revisão descreve alguns métodos usados para análise conformacional e as implicações ao usarem algumas conformações selecionadas em QSAR. Um estudo de caso foi desenvolvido para o ácido 2,4-diclorofenóxi acético (2,4-D), um herbicida amplamente usado que se liga à enzima TIR1 ubiquitina ligase. O uso de tal aproximação e cálculos semi-empíricos não alcançou todos os mínimos possíveis para o 2,4-D. Além disso, as conformações e respectivas energias obtidas pelo método semi-empírico AM1 não concordam com as tendências calculadas em nível DFT. Resultados similares foram obtidos para o ânion carboxilato, que é a forma bioativa do 2,4-D. Finalmente, a estrutura cristalina e bioativa do 2,4-D não foi encontrada como um mínimo de energia usando MonteCarlo/AM1 e, de acordo com otimização em nível B3LYP/aug-cc-pVDZ, tem população similar ao outro confôrmero em solução aquosa implícita. Portanto, métodos para relação quantitativa entre estrutura e atividade (QSAR) baseados na estrutura química tridimensional não são fundamentais para fornecer modelos preditivos...

3D perspective into MIA‐QSAR: A case for anti‐HCV agents

“…The color system employed is the RGB (24 bits ); therefore, the pixels can assume values that varies from “0” (black color) to 765 (white color), since each pixel in this system is a result of the combination of three color channels (red, green, and blue) and each of these channels assumes values that vary from 0 to 255. These considerations have shown satisfactory outcomes, often comparable to those results obtained using 3D methodologies (Daré, Barigye, & Freitas, ; de Freitas & Ramalho, ; Freitas et al., ; Guimarães et al., ). Moreover, MIA‐QSAR also includes a graphical tool denominated MIA‐plot that allows the user to obtain a detailed chemical interpretation of the regression models (Barigye, Duarte, Nunes, & Freitas, ; Borges & Barigye, ).…”

“…The main advantages of this approach are (a) the parameters (descriptors) contain simple and efficient information of the molecular structure, (b) they are also invariant to molecule roto‐translations, and, finally, (c) these parameters can be obtained avoiding geometry optimization (Consonni & Todeschini, ). On the other hand, the 2D models, although reliable, are not easily interpretable in a meaningful way, that is, it is not always possible to find a biochemical/physicochemical explanation for the propriety under analysis based on the QSAR model (de Freitas & Ramalho, ).…”

“…These methods, although efficient in their tasks, present a high level of complications, which contributes to the 3D‐QSAR complexity (Verma et al., ). Furthermore, 3D methods usually employ conformational screening and structural alignment rules that do not consider the biological target itself, which can lead to incoherent conclusions (de Freitas & Ramalho, ).…”

Intramolecular interactions contributing for the conformational preference of bioactive diphenhydramine: Manifestation of the gauche effect

“…for the herbicide 2,4-D, whose bioactive conformation is different from that of the free compound [13], 2 can be useful to probe for the rule of intramolecular interactions on the bioactive conformation of molecules. Indeed, both diphenhydramine molecules complexed in the crystal histamine methyltransferase enzyme (PDB code: 2AOT, Fig.…”

“…In addition, the protonated diphenhydramine was experimentally and theoretically studied to give insight about the role of the electrostatic gauche effect in this cation, and also because it is not explicit in the crystal if the bioactive compound is protonated or not [12]. The outcomes from this study can be useful to understand the role of intramolecular interactions as governing factors of the conformational preferences in a biological environment, since an earlier work showed that the bioactive conformation of 2,4-dichlorophenoxyacetic acid (2,4-D), an herbicide that binds the TIR1 ubiquitin ligase enzyme, does not match the structure of the calculated most stable conformer [13].…”