Triple-layered QSAR studies on substituted 1,2,4-trioxanes as potential antimalarial agents: superiority of the quantitative pharmacophore-based alignment over common substructure-based alignment

This study reports the utilization of three approaches – pharmacophore, CoMFA/CoMSIA and HQSAR studies – to identify the essential structural requirements in 3D chemical space for the modulation of the antimalarial activity of substituted 1,2,4-trioxanes. The superiority of quantitative pharmacophore-based alignment (QuantitativePBA) over global minima energy conformer-based alignment (GMCBA) has been reported in CoMFA and CoMSIA studies. The developed models showed good statistical significance in internal validation (q ², group cross-validation and bootstrapping) and performed very well in predicting the antimalarial activity of test set compounds. Structural features in terms of their steric, electrostatic and hydrophobic interactions in 3D space have been found to be important for the antimalarial activity of substituted 1,2,4-trioxanes. Further, the HQSAR studies based on the same training and test set acted as an additional tool to find the sub-structural fingerprints of substituted 1,2,4-trioxanes for their antimalarial activity. Together, these studies may facilitate the design and discovery of new substituted 1,2,4-trioxanes with potent antimalarial activity.     

Sphingosine kinase 1 (SK1) allosteric inhibitors that target the dimerization site

The sphingosine kinase 1 (SK1)/sphingosine-1-phosphate (S1P) signaling pathway is a crucial target for numerous human diseases from cancer to cardiovascular diseases. However, available SK1 inhibitors that target the active site suffer from poor potency, selectivity and pharmacokinetic properties. The selectivity issue of the kinases, which share a highly-conserved ATP-pocket, can be overcome by targeting the less-conserved allosteric sites. SK1 is known to function minimally as a dimer; however, the crystal structure of the SK1 dimer has not been determined. In this study, a template-based algorithm implemented in PRISM was used to predict the SK1 dimer structure and then the possible allosteric sites at the dimer interface were determined via SiteMap. These sites were used in a virtual screening campaign that includes an integrated workflow of structure-based pharmacophore modeling, virtual screening, molecular docking, re-screening of common scaffolds to propose a series of compounds with different scaffolds as potential allosteric SK1 inhibitors. Finally, the stability of the SK1-ligand complexes was analyzed by molecular dynamics simulations. As a final outcome, ligand 7 having a 4,9-dihydro-1H-purine scaffold and ligand 12 having a 2,3,4,9-tetrahydro-1H-β-carboline scaffold were found to be potential selective inhibitors for SK1.     

Design,Synthesis and Evaluation of Substituted N-(3-Arylpropyl)-9,10-dihydro-9-oxoacridine-4-carboxamides as Potent MDR Reversal Agents in Cancer

A novel class of molecules with structure N‐(3‐arylpropyl)‐9,10‐dihydro‐9‐oxoacridine‐4‐carboxamides ( 20 – 29 ) were designed by generating a pharmacophore for potent MDR reversal activity using phase drug design software. The designed molecules were synthesized by a novel synthesis route and evaluated for their inhibitory effects on the transport activity of P‐glycoprotein (P‐gp) by standard Hoechst 33342 assay method. Based on the pIC₅₀ values of ten title compounds screened, three compounds exhibited better activity as compared to Verapamil used as standard.     

Singular value decomposition of torsional angles of analogs of the dopamine reuptake inhibitor GBR 12909

Analysis of large, flexible molecules, such as the dopamine reuptake inhibitor GBR 12909 (1), is complicated by the fact that they can take on a wide range of closely related conformations. The first step in the analysis is to classify the conformers into groups. Here, Singular Value Decomposition (SVD) was used to group conformations of GBR 12909 analogs by the similarity of their nonring torsional angles. The significance of the present work, the first application of SVD to the analysis of very flexible molecules, lies in the development of a novel scaling technique for circular data and in the grouping of molecular conformations using a technique that is independent of molecular alignment. Over 700 conformers each of a piperazine (2) and piperidine (3) analog of 1 were studied. Analysis of the score and loading plots showed that the conformers of 2 separate into three large groups due to torsional angles on the naphthalene side of the molecule, whereas those of 3 separate into nine groups due to torsional angles on the bisphenyl side of the molecule. These differences are due to nitrogen inversion at the unprotonated piperazinyl nitrogen of 2, which results in a different ensemble of conformers than those of 3, where no inversion is possible at the corresponding piperidinyl carbon.     

Predictive models for tyrosinase inhibitors: Challenges from heterogeneous activity data determined by different experimental protocols

Quantitative Structure-Activity Relationship (QSAR) models of tyrosinase inhibitors were built using Random Forest (RF) algorithm and evaluated by the out-of-bag estimation (R²_OOB) and 10-fold cross validation (Q²_CV). We found that the performances of QSAR models were closely correlated with the systematic errors of inhibitory activities of tyrosinase inhibitors arising from the different measuring protocols. By defining ERR_sys, outliers with larger errors can be efficiently identified and removed from heterogeneous activity data. A reasonable QSAR model (R²_OOB of 0.74 and Q²_CV of 0.80) was obtained by the exclusion of 13 outliers with larger systematic errors. It is a clear example of the challenge for QSAR model that can overwhelm heterogeneous data from different experimental protocols.     

Synthesis and evaluation of the bioactivity of simplified analogs of the seco-pseudopterosins; progress toward determining a pharmacophore

The pseudopterosins are marine natural products that display significant anti-inflammatory and wound healing properties. We describe the synthesis of six structural analogs of the seco-pseudopterosin-like core that are devoid of all but one of the stereocenters found in the carbocyclic core of the natural products. Our targets were selected in an attempt to identify the minimal pharmacophore for the pseudopterosins and their seco analogs. A deliberate effort was made to utilize a conservative synthetic approach based upon the use of well-established reactions, which enabled us to develop routes that proved to be efficient, practical, and easy to implement. The results of several bioassays, including an assessment of the ability to inhibit phagocytosis and to competitively bind to the adenosine receptor A_2A, demonstrate that greatly simplified structural analogs of the pseudopterosins and their seco forms are capable of maintaining several of the important bioactivities that characterize the natural products, and do so with comparable efficacy. Those systems bearing two rather than one oxygen atom appended directly to the aromatic ring are the more effective binding agents. This observation may provide a significant clue regarding the key structural features of the minimal pharmacophore.     

General model of the opiate pharmacophore

Analysis of experimental data on the correlation of agonistic and antagonistic properties of molecules of the opiate receptor (OR) ligands of various structural classes and the use of the method of superposition of three-dimensional structures allowed one to single out two regions of the opiate pharmacophore in which hydrophobic interactions are implemented fixing molecules of the OR ligands close to the intercellular membrane and transforming them into “pure” agonists. A set of geometrical parameters characterizing arrangement of these regions in space is defined. This set can be used as a criterion for evaluation of the correlation of agonistic and antagonistic properties in the modeling of new types of OR ligands. For Part 1, see Ref. 1. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1253–1260, June, 2008.     

The active analog approach applied to the pharmacophore identification of benzodiazepine receptor ligands

Summary Applied to seven potent benzodiazepine-receptor ligands belonging to chemically different classes, the active analog approach allowed the stepwise identification of the pharmacophoric pattern associated with the recognition by the benzodiazepine receptor.A unique pharmacophore model was derived which involves six critical zones: (a) a -electron rich aromatic (PAR) zone; (b) two electron-rich zones ₁ and ₂ placed at 5.0 and 4.5 Å respectively from the reference centroid in the PAR zone; (c) a freely rotating aromatic ring (FRA) region; (d) an out-of-plane region (OPR), strongly associated with agonist properties; and (e) an additional hydrophobic region (AHR).The model accommodates all presently known ligands of the benzodiazepine receptor, identifies sensitivity to steric hindrance close to the ₁ zone, accounts forR andS differential affinities and distinguishes requirements for agonist versus non-agonist activity profiles.Abbreviations Pyrazoloquinolines CGS (2-phenyl-2,5-dihydro pyrazolo [4,3-c] quinoline-3 (3H)-one) - Cinnolinones CIN (2-(4-methoxyphenyl)-benzo [h] 3-cinnolinone - Triazolophthalazines TZPH (3-(4-methoxyphenyl)-6 pyrrolidinotriazolo [4,3-a] phthalazine - Cyclopyrrolones RP 27267, CLO ([6-(5-chloro-2-pyridyl)-6,7-dihydro-7 oxo-5H-pyrrolo [3,4-b]pyrazin-5-yl] 4-methyl-l-piperazine carboxylate) - Phenylquinolines PK (phenyl-2 (morpholinocarbonyl methyl oxy)-4 quinoline - -Carbolines BCC (3-carboethoxy--carboline) - Benzodiazepines: Diazepam DZ (7-chloro-1,3-dihydro-1-methyl-5 phenyl-2H-1,4-benzodiazepin-2-one)     

距离比较法(DISCO)构建ALS抑制剂药效团模型

在乙酰乳酸合成酶（ALS）三维结构未知的情况下,利用距离比较法（DISCO） ,将10 个结构特征具有代表性的ALS抑制剂的分子构象进行叠合,建立了可能的 药效团模型,并初步验证了模型的可靠性。