QSAR based on the D structures of ligands plays an

QSAR based on the 3D structures of ligands plays an important role in the ligand-based drug discovery and design [12]. Comparative molecular field analysis, CoMFA [11], and comparative molecular similarity index analysis, CoMSIA [12] are among the most popular QSAR models. They focus on changes in 3D structures features such as steric, electrostatic and ABT-888 properties and they employ the statistical techniques to correlate them with biological activities.
Material and methods
Results and discussion The predicted and experimental activity values and their residual values for both the training and test sets by employing CoMFA and CoMSIA models are given in Table 2.
Conclusion A combination of two computational techniques were applied to study a series of nineteen 7,8-dialkylpyrrolo-[3,2-f] Quinazoline derivatives, not only to generate highly statistical and predictive 3D-QSAR models, but to explore the interaction mechanism between the Quinazoline derivatives and the DHFR enzyme. CoMFA (Q2 = 0.64, R2 = 0.96) and CoMSIA (Q2 = 0.72, R2 = 0.93) approach produce equally good models in term of several rigorous statistical keys, such as Q2 and R2test, for both the internal and external data sets. Graphical interpretation of the results provided by those models revealed that the binding affinity of this class of compounds could be greatly influenced by the substituents in R1 and R2 positions of the basic skeleton. Molecular docking simulation was used to better understand the binding mechanism and produce the binding poses of these compounds to DHFR enzyme, in addition to complete obtained results from 3D-QSAR studies. Further, all those studies lead to one result that the Quinozaline skeleton is the key of the DHFR inhibitor behavior in the studied compounds, so, for more potent drugs the R1 must be an adaptive bulky alkyl group as an Et, i-Pr or Cyclopr and the R2 it\'s preferred to be a bulky alkyl group like a CEt3 or CHEt2. A good consistently between the molecular docking and CoMFA and CoMSIA contour maps confirms the robustness and the reliability of the proposed models.
Acknowledgments
Introduction The B vitamin folate has been associated with a variety of complications during pregnancy e.g., orofacial clefts [1], congenital heart defects [2] and neural tube defects (NTDs) [3]. The most obvious and extensively studied birth defects in relation to folate are NTDs. Nowadays it is well established that periconceptional folate supplementation reduces the occurrence and recurrence risk of NTDs by 50–70 % [3], [4], [5]. The search for the molecular genetic basis of this beneficial effect of folic acid however continues [6]. DHFR reduces dihydrofolate (DHF) that is formed during thymidylate (dTMP) synthesis back into tetrahydrofolate (THF) and hereby stimulates folate turnover, the production of dTMPs and hence DNA synthesis. These processes are all essential for rapid cell growth and division. An adequate folate turnover is also important for proper methylation of DNA, RNA and proteins, since folate donates its methyl group to homocysteine that is converted into S-adenosylmethionine after remethylation to methionine. S-Adenosylmethionine is one of the most important methyl donors in the body. In addition, DHFR reduces folic acid present in vitamin supplements and food fortification so that it becomes metabolically active. The importance of DHFR is further illustrated by the observation that the coding region of the DHFR gene harbors no variation in 20 individuals whose DHFR gene was sequenced [7]. Recently, Johnson et al. described a 19-bp deletion in intron-1 of the DHFR gene and reported an association between this deletion and an increased risk of having a spina bifida affected child in a population consisting of 61 spina bifida patients, 50 mothers and 46 fathers of a spina bifida affected child and 219 controls (OR: 2.0; 95%CI: 0.94–4.29) [8]. They hypothesize that the deletion removes a possible transcription factor binding site for Sp1, thereby decreasing DHFR expression. A 9-bp repeat in exon 1 of the mutS homolog 3 (MSH3) gene identified by Nakajima et al. [9] was recently described to be also located in the 5′ untranslated region (UTR) of DHFR and therefore might interfere with DHFR expression [7].