The widely abused psychostimulant cocaine is thought to elicit its reinforcing effects primarily via inhibition of the neuronal dopamine transporter (DAT). However, not all DAT inhibitors share cocaine’s behavioral profile, despite similar or greater affinity for the DAT. This may be due to differential molecular interactions with the DAT. Our previous work using transporter mutants with altered conformational equilibrium (W84L and D313N) indicated that benztropine and GBR12909 interact with the DAT in a different manner than cocaine. Here, we expand upon these previous findings, studying a number of structurally different DAT inhibitors for their ability to inhibit [3H]CFT binding to wild‐type, W84L and D313N transporters. We systematically tested structural intermediates between cocaine and benztropine, structural hybrids of benztropine and GBR12909 and a number of other structurally heterologous inhibitors. Derivatives of the stimulant desoxypipradrol (2‐benzhydrylpiperidine) exhibited a cocaine‐like binding profile with respect to mutation, whereas compounds possessing the diphenylmethoxy moiety of benztropine and GBR12909 were dissimilar to cocaine‐like compounds. In tests with specific isomers of cocaine and tropane analogues, compounds with 3α stereochemistry tended to exhibit benztropine‐like binding, whereas those with 3β stereochemistry were more cocaine‐like. Our results point to the importance of specific molecular features – most notably the presence of a diphenylmethoxy moiety – in determining a compound’s binding profile. This study furthers the concept of using DAT mutants to differentiate cocaine‐like inhibitors from atypical inhibitors in vitro. Further studies of the molecular features that define inhibitor–transporter interaction could lead to the development of DAT inhibitors with differential clinical utility.

Reverse or inverse docking is proving to be a powerful tool for drug repositioning and drug rescue. It involves docking a small-molecule drug/ligand in the potential binding cavities of a set of clinically relevant macromolecular targets. Detailed analyses of the binding characteristics lead to ranking of the targets according to the tightness of binding. This process can potentially identify novel molecular targets for the drug/ligand which may be relevant for its mechanism of action and/or side effect profile. Another potential application of reverse docking is during the lead discovery and optimization stages of the drug-discovery cycle. This review summarizes the state-of-the-art and future prospects of the reverse docking with particular emphasis on computational molecular design.

Three-dimensional quantitative structure-activity relationship (3D QSAR) methods, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), were applied on a series of 1,4-dihydropyridines possessing antitubercular activity. The study was performed using 33 compounds, in which 22 molecules were used for the derivation of the 3D QSAR models (training set) and 11 molecules were used to evaluate the predictive ability of the derived models (test set). Superimpositions were performed using three alignment rules: atom-based fitting, SYBYL QSAR rigid body field fit of the steric and electrostatic fields of the molecules, and flexible fitting (multifit). Both methods were analyzed in terms of their predictive abilities and produced comparable results with high internal as well as external predictivities. Steric and electrostatic fields of the inhibitors were found to be relevant descriptors for SAR. Use of lowest unoccupied molecular orbital energies or ClogP as additional descriptors in the QSAR table did not improve the significance of the 3D QSAR models. Both CoMFA and CoMSIA models based on multifit alignment showed better correlative and predictive properties than other models. A QSAR study using genetic function approximation was also performed for the same set of molecules using different types of physicochemical descriptors to deal with cell-based activity data. The QSAR models revealed the importance of spatial properties and conformational flexibility of side chains for antitubercular activity. Inclusion of fractional polar solvent accessible surface area as a descriptor in the model generation resulted in models with significant internal and external predictivities for the same test set molecules, which may support the possible mode of action of these compounds.

Here we report structure-activity relationship study of a novel hybrid series of compounds where structural alteration of aromatic hydrophobic moieties connected to the piperazine ring and bioisosteric replacement of the aromatic tetralin moieties were carried out. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated spiperone to evaluate inhibition constants (Ki). Functional activity of selected compounds in stimulating GTPγS binding was assessed with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors. SAR results identified compound (−)-24c (D-301) as one of the lead molecules with preferential agonist activity for D3 receptor (EC50 (GTPγS); D3 = 0.52 nM; D2/D3 (EC50): 223). Compounds (−)-24b and (−)-24c exhibited potent radical scavenging activity. The two lead compounds (−)-24b and (−)-24c exhibited high in vivo activity in two Parkinson’s disease (PD) animal models, reserpinized rat model and 6-OH-DA induced unilaterally lesioned rat model. Future studies will explore potential use of these compounds in the neuroprotective therapy for PD.

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A series of structurally constrained analogues based on hybrid compounds containing octahydrobenzo[g or f]quinoline moieties were designed, synthesized and characterized for their binding to dopamine D2 and D3 receptors expressed in HEK-293 cells. Among the newly developed constrained molecules, trans-octahydrobenzo[f]-quinolin-7-ol (8) exhibited the highest affinity for D2 and D3 receptors; the (−)-isomer being the eutomer. Interestingly, this hybrid constrained version 8 showed significant affinity over the corresponding non-hybrid version 1 (representing a constrained version of the aminotetralin structure only) when assayed under same conditions (K i 49.1 and 14.9 nM for 8 vs. 380 and 96.0 nM for 1 at D2 and D3, respectively). Similar results were found with other lead hybrid compounds, indicating a contribution of the piperazine moiety in the observed enhanced affinity. Based on the data of new lead constrained derivatives and other lead hybrid derivatives developed by us, a unique pharmacophore model was proposed consisting of three pharmacophoric centers, two with aromatic/hydrophobic and one with cationic features.