Piperidine Analogues Research Articles

A Computational Analysis of the Proton Affinity and the Hydration of TEMPO and Its Piperidine Analogs.

The study investigated the impact of protonation and hydration on the geometry of nitroxide radicals using B3LYP and M06-2X methods. Results indicated that TEMPO exhibited the highest proton affinity in comparison to TEMPOL and TEMPONE. Two pathways contribute to hydrated protonated molecules. TEMPO shows lower first enthalpies of hydration (ΔH1-M), indicating stronger H-bonding interactions, while TEMPONE shows higher values, indicating weaker interactions with H2O. Solvent effects affect charge distribution by decreasing their atomic charge. Spin density (SD) is primarily concentrated in the NO segment, with minimal water molecule contamination. Protonation increases SD on N-atom, while hydration causes a more pronounced redistribution for water molecules. The stability of the dipolar structure (>N·+-O-) is evident in SD redistributions. The frontier molecular orbital (FMO) analysis of TEMPONE reveals a minimum EHOMO-LUMO gap (EH-L), enhancing the piperidine ring's reactivity. TEMPO is the most nucleophilic species, while TEMPONE exhibits strong electrophilicity. Transitioning from NO radicals to protonated forms increases the EH-L gap, indicating protonation stabilizes FMOs. Increased water molecules make the molecule less reactive, while increasing hydration decreases this energy gap, making the molecule more reactive. A smaller EH-L gap indicates the compound becomes softer and more prone to electron density and reactivity changes.

Guanidine-to-piperidine switch affords high affinity small molecule NPFF ligands with preference for NPFF1-R and NPFF2-R subtypes

The Neuropeptide FF (NPFF) receptor system is known to modulate opioid actions and has been shown to mediate opioid-induced hyperalgesia and tolerance. The lack of subtype selective small molecule compounds has hampered further exploration of the pharmacology of this receptor system. The vast majority of available NPFF ligands possess a highly basic guanidine group, including our lead small molecule, MES304. Despite providing strong receptor binding, the guanidine group presents a potential pharmacokinetic liability for in vivo pharmacological tool development. Through structure-activity relationship exploration, we were able to modify our lead molecule MES304 to arrive at guanidine-free NPFF ligands. The novel piperidine analogues 8b and 16a are among the few non-guanidine based NPFF ligands known in literature. Both compounds displayed nanomolar NPFF-R binding affinity approaching that of the parent molecule. Moreover, while MES304 was non-subtype selective, these two analogues presented new starting points for subtype selective scaffolds, whereby 8b displayed a 15-fold preference for NPFF1-R, and 16a demonstrated an 8-fold preference for NPFF2-R. Both analogues showed no agonist activity on either receptor subtype in the in vitro functional activity assay, while 8b displayed antagonistic properties at NPFF1-R. The calculated physicochemical properties of 8b and 16a were also shown to be more favorable for in vivo tool design. These results indicate the possibility of developing potent, subtype selective NPFF ligands devoid of a guanidine functionality.

Computational study of the piperidine and FtsZ interaction in Salmonella Typhi: implications for disrupting cell division machinery

FtsZ, a bacterial cell division protein, is essential for assembling the contractile Z-ring crucial in bacterial cytokinesis. Consequently, inhibiting FtsZ could impede proto-filaments, disrupting FtsZ and other associated proteins vital for cell division machinery. Conduct an in-silico drug interaction study to identify novel drug candidates that inhibit the FtsZ protein, aiming to prevent Multi-Drug Resistant (MDR) Salmonella Typhi. Data mining was performed based on piperidine compounds, which were subsequently screened for safe pharmacokinetic profiles. Compounds that met favorable drug-likeness criteria underwent virtual screening against the FtsZ drug target. Two compounds were chosen for molecular docking and molecular dynamic simulation to verify the binding affinity and stability between the target protein and the potential compounds. The 400 isoforms of piperidine analogues were curated, among them potent compound ZINC000000005416 found to possess high binding affinity (-8.49 kcal/mol) and low dissociation constant (0.597 µM). The highest binding affinity shown by ZINC000000005416 was validated by hydrogen bonds, hydrophobic interaction, and salt bridges with the functional domain of the cell division regulatory protein. Docking profiles, when correlated with molecular dynamic simulation (MDS) depicted stable trajectories and compatible conformational changes in the FtsZ-ZINC000000005416 complex. The stable simulated trajectories were validated through free-energy calculations using the Molecular Mechanics-Poisson Boltzmann Surface Area (MM/PBSA) module. Low energy conformations, although the simulation trajectory confirmed the stable ZINC000000005416-FtsZ interaction, which encouraged experimental validations. This study encourages further exploration of the compound ZINC000000005416 as a drug candidate inhibiting FtsZ protein against MDR Salmonella Typhi. Communicated by Ramaswamy H. Sarma

Synthesis of Piperidine‐based Derivatives as Red Emitting Lu‐minescent Materials

AbstractOrganic fluorescent materials have become increasingly attractive due to the requirements of green chemistry. In this study, the synthetic route of piperidine‐based fluorescent materials was optimized with good to excellent yields. 37 fluorescent compounds were achieved with emission wavelength at 540–670 nm and chromogenic changed from green to standard red. The fluorescence quantum yields of 5 a, 5 ab, and 5 af were 1.96 %, 0.97 %, and 5.13 %, respectively. The relationship between the structure and luminescent properties has also been systematically discussed. This work presents the possibility of utilizing piperidine analogues to develop fluorescent probes in biological imaging, display devices and other related fields.

Piperidine and piperazine analogs in action: zinc(ii)-mediated formation of amidines

Secondary cyclic amines such as piperazine and its substituted derivatives were reacted in the presence of zinc(ii) with acetonitrile to prepare a series of complexes. The formation of a zinc(ii) complex with acetamidine was also investigated.

Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile.

Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in the preclinical models of psychostimulant use disorders (PSUD). In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (JJC8-091, 3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. Improvements in DAT affinity and metabolic stability were desirable for discovering pipeline drug candidates. Thus, a series of 1-(4-(2-bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines were synthesized and evaluated for binding affinities at DAT and the serotonin transporter (SERT). Replacement of the piperazine with either a homopiperazine or a piperidine ring system was well tolerated at DAT (Ki range = 3-382 nM). However, only the piperidine analogues (20a-d) showed improved metabolic stability in rat liver microsomes as compared to the previously reported analogues. Compounds 12b and 20a appeared to retain an atypical DAT inhibitor profile, based on negligible locomotor activity in mice and molecular modeling that predicts binding to an inward-facing conformation of DAT.

Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC.

The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and piperidine scaffolds such as (+)-BNM-III-170 and (S)-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp368 Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the infection of difficult-to-neutralize tier-2 viruses and sensitize infected cells to ADCC mediated by HIV+ plasma. Moreover, the new analogs formed an H-bond with the α-carboxylic acid group of Asp368, opening a new avenue to enlarge the breadth of this family of anti-Env small molecules. Overall, the new structural and biological attributes of these molecules make them good candidates for strategies aimed at the elimination of HIV-1-infected cells.

Metal‐Free Catalytic Functionalization of Second −Csp2−H Bond of 1‐Methyl Pyrrole Using Bishomocubane‐Derived Aminoborane Frustrated Lewis Pairs: A Computational Study

AbstractBishomocubane, as a molecular scaffold, has been designed to functionalize the −Csp2−H bond of 1‐methyl pyrrole. The newly designed molecular scaffold showed noteworthy improvements in the reaction energetics than the phenylene scaffold. The DFT (ωB97XD/6‐31+G(d,p)) calculations revealed that the dimethyl amine (A) and piperidine (B) analogues of bishomocubane frustrated Lewis pairs (FLP) can catalyze the first −Csp2−H functionalization much more easily than that of the phenylene FLP. The previous results showed that the second −Csp2−H functionalization was found to be energetically difficult. The DFT calculations suggest that the piperidine analogue of bishomocubane, 1‐Pip‐2‐BH2‐C10H10 (B), can lead the second −Csp2−H functionalization facile than the reported FLPs. The rate‐determining step of the second −Csp2−H functionalization is significantly lower with the catalyst (B) by ∼9.0 kcal/mol compared to the phenylene catalyst (II). The improved reactivity of bishomocubane FLPs has been examined with molecular electrostatic potential (MESP) analysis and the conceptual density functional theory (CDFT) calculations. The hyperconjugative stabilization interaction (n→σ*) and the strain relief between the Lewis pairs play a crucial role in the stability of rate‐determining transition states. This study reveals that saturated hydrocarbon scaffolds are promising candidates as FLP catalysts in such reactions.

Design, synthesis, in vitro and in silico characterization of plastoquinone analogs containing piperidine moiety as antimicrobial agents

The design and development of novel antibacterial and/or antifungal lead structures are urgently required to cope with the increasing antimicrobial resistance. Inspired by the literature and our previous studies, we designed and synthesized new Plastoquinone analogs (PQ1–12) containing piperidine moiety via one-pot reaction of commercially available 2,3-dimethylhydroquinone (1) with piperidine analogs by varying a heteroatom within the piperidine moiety or an alkyl group and (hetero)cyclic structure attached to the piperidine moiety. The chemical structures of the PQ analogs were determined by spectroscopic methods (FTIR, NMR, Mass, and X-ray). The antimicrobial activity of the PQ analogs was investigated against both bacterial and fungal strains. The tested PQ analogs showed significant antibacterial activity and weak to moderate antifungal activity. PQ2 and PQ7 exhibited favorably strong interactions with fungal CYP51 and S. aureus DNA gyrase, respectively, in silico. Both compounds displayed favorable physicochemical and pharmacokinetic properties.

Identification of new pyrazolyl piperidine molecules as factor Xa inhibitors: Design, synthesis, in silico, and biological evaluation

Coagulation factor Xa (FXa), a serine endopeptidase is a common coagulation factor activated as a result of the initiation of both intrinsic and extrinsic blood coagulation pathways. Hence, FXa has been regarded as an important pharmaceutical target for the treatment of thrombotic disorders. In this study, we reported the design and synthesis of pyrazolyl piperidine analogs 4(a–h) as a new class of anticoagulant drug candidates. Among the synthesized analogs 4(a–h), compound 4a consisting of the 4-chlorophenyl substitution displayed the highest in vitro FXa inhibition activity with an IC50 value of 13.4 nM. The PT and aPTT assay indicated that compound 4a showed good anticoagulation activity compared to Heparin. Furthermore, docking studies suggested that the synthesized analogs displayed binding modes similar to the cocrystallized Rivaroxaban ligand. In addition, in-silico ADMET and DFT studies were carried out for all the designed compounds. Together, our study suggests that the compound (4a) displayed anti-coagulant activity through the inhibition of FXa.

Nickel-catalyzed asymmetric arylative cyclization of N-alkynones: Efficient access to 1,2,3,6-tetrahydropyridines with a tertiary alcohol

Nickel/(S)-t-Bu-PHOX complex catalyzed asymmetric arylative cyclization of N-alkynones has been achieved, delivering 1,2,3,6-tetrahydropyridines containing a chiral tertiary alcohol in high yields and excellent enantioselectivities, which provides efficient access to chiral tetrahydropyridine and piperidine analogues.

Diastereoselective Reductive Cyclization of Allene‐Tethered Ketoamines via Copper‐Catalyzed Cascade Carboboronation and Protodeborylation

A copper‐catalyzed cascade process has been developed for the synthesis of 3‐hydroxypyrrolidine derivatives in a highly diastereoselective manner. The reaction proceeded via borylative allyl copper intermediate formation from allenes; the intermediate underwent intramolecular diastereoselective cyclization followed by cascade copper‐catalyzed protodeborylation, to give 3‐hydroxypyrrolidines. This method could be extended to the synthesis of six‐membered piperidine analogs. A series of control experiments were carried out to confirm the Cu‐catalyzed facile protodeborylation of borylated homoallylic alcohols at room temperature.

Investigation of Experimental and In Silico Physicochemical Properties of Thiazole-Pyridinium Anti-Acetylcholinesterase Derivatives with Potential Anti-Alzheimer’s Activity

Background: Physicochemical properties play important role in fundamental issues like absorption and distribution of pharmaceuticals to the target tissue. This is particularly importantfor drugs acting in central nervous system (CNS). In this study, physicochemical properties of previously synthesized thiazole-pyridinium derivatives with anti-acetylcholinesterase activity and possible anti-Alzheimer effect were studied. Methods: Partition coefficient (n-octanol/water) and chromatographic Rf values for the studied compounds were determined using shake flask and high performance thin layer chromatography(HPTLC) methods, respectively. Different druglikeness properties of the compounds were also calculated using available software and web-servers. Results: The experimentally determined logarithm of partition coefficients (log P) for the studied compounds were in the range of -1.00 to -0.38. The Rf values for the studied compounds under the applied chromatographic condition ranged between 0.38 to 0.58. Moreover, calculated physicochemical properties, and druglikeness scores of the studied thiazole-pyridiniumderivatives and matching piperidine analogues were predicted. Furthermore, some ADMETfeatures of studied compounds like toxicity and metabolism by CYP450 (2C9, 2D6, 3A4, 1A2and 2C19) enzymes were predicted. Conclusion: The ranges of experimental and calculated LogP values for the studied thiazolepyridinumswere close. However, the determined Rf values showed relatively better correlation to the predicted LogP values indicating the suitability of used chromatographic method for comparing the lipophilicity of the positively charged pyridinium derivatives. The studied compounds were predicted to pass GI membrane and reach the CNS where they can exert their effects. In silico studies indicate that the piperidine counterparts of the studied thiazolepyridiniumsmay represent anti-Alzheimer agents with improved druglikeness properties.

Design, Synthesis, and Structure-Activity Relationship Exploration of Alkyl/Phenylalkyl Piperidine Analogues as Novel Highly Potent and Selective μ Opioid Receptor Agonists.

Pain was implicated in many diseases. Despite effectiveness to treat moderate to severe pain, opioid analgesics elicited many side effects, greatly limiting their prescription in clinics. Based on M1, an active metabolite of tramadol, 3-((dimethylamino)methyl)-4-(3-hydroxyphenyl)piperidin-4-ol analogues were designed, synthesized, and evaluated in vitro. Among all the compounds tested, compound 23 was found to be a novel, highly selective, and potent MOR agonist (KiMOR = 0.0034 nM, EC50MOR = 0.68 nM, Emax = 206.5%; KiDOR = 41.67 nM; KiKOR = 7.9 nM). Structure-activity relationship exploration showed that the linker between the piperidine ring and the phenyl ring as well as substituent pattern of the phenyl ring played a pivotal role in binding affinity and selectivity. (3R, 4S)-23 (KiMOR = 0.0021 ± 0.0001 nM, EC50MOR = 0.0013 ± 0.0001 nM, Emax = 209.1 ± 1.4%; KiDOR = 18.4 ± 0.7 nM, EC50DOR = 74.5 ± 2.8 nM, Emax = 267.1 ± 1.4%; KiKOR = 25.8 ± 0.2 nM, EC50DOR = 116.2 ± 4.4 nM, Emax = 209.5 ± 1.4%) had more potent activity for opioid receptors than its enantiomer (3S, 4R)-23 and was found to be a potent, highly selective MOR agonist with novel scaffold. High binding affinity and selectivity of (3R, 4S)-23 for MOR over KOR and DOR and its mechanism of activating MOR were proposed by docking and molecular dynamics simulations, respectively.

Profiling the antidepressant properties of phenyl piperidine derivatives as inhibitors of serotonin transporter (SERT) via cheminformatics modeling, molecular docking and ADMET predictions.

The inhibition of serotonin transporter (SERT) has been considered to be a good target for the treatment of mood disorders (depression). The present study employed cheminformatics modeling, molecular docking analysis and ADMET predictions approaches on some Phenyl piperidine derivatives reported as inhibitors of serotonin transporter to determine the structural and physicochemical parameters of the compounds responsible for the inhibition, to elucidate the binding interactions between the receptor and the ligands and to predict the ADMET properties of the compounds as antidepressant agents. A validated cheminformatics model was developed using Density Functional Theory (DFT/B3LYP/6-31G*) by utilizing the Genetic Function Algorithm for variable selections. The obtained statistical parameters of the model (R2Train = 0.8572, R2Test = 0.678 and cR2p= 0.763) showed that the model was well predicted, robust, reliable and very stable. Similarly, five molecular descriptors (AATS8v, GATS1e, SpMAD_Dzs, SP-7 and RDF135v) were found to be significantly correlated to the inhibitory activity of the compounds in the developed model. Likewise, the molecular docking analysis elucidates the important interactions between the amino acid residues at the active site of the receptor between the ligands. Four ligands (1,2,5 and 6) were selected which portend higher binding affinity (-10.1, -10.2, -10.4 and -10.5 kcal/mol) with the lower RMSD values compared to the standard drug (Brexpiprazole) with a smaller binding affinity (-8.1 kcal/ mol) and elevated RMSD value. All the selected compounds revealed to be orally bioavailable and pharmacologically active because none of the compounds violate Lipinski's rule of five. The ADMET predictions show that all the selected compounds including Brexpiprazole were non-inhibitors of CYP3A4 and CYP2D6 cytochrome P450 enzymes with attributes of good blood-brain barrier (BBB) penetration, excellent gastrointestinal (GI) absorption and are unlikely to exhibit cardiovascular toxicity (hERG toxicity). As a consequence, the methodology employed in this study and the obtained results could serve as a reliable framework to uncover novel Phenyl piperidine analogues and for the rational design of potential inhibitors of the serotonin transporter (SERT) as antidepressant agents.

Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study.

A series of potent HIV-1 protease inhibitors, containing diverse piperidine analogues as the P2-ligands, 4-substituted phenylsulfonamides as the P2’-ligands and a hydrophobic cyclopropyl group as the P1’-ligand, were designed, synthesized and evaluated in this work. Among these twenty-four target compounds, many of them exhibited excellent activity against HIV-1 protease with half maximal inhibitory concentration (IC50) values below 20 nM. Particularly, compound 22a containing a (R)-piperidine-3-carboxamide as the P2-ligand and a 4-methoxylphenylsulfonamide as the P2’-ligand exhibited the most effective inhibitory activity with an IC50 value of 3.61 nM. More importantly, 22a exhibited activity with inhibition of 42% and 26% against wild-type and Darunavir (DRV)-resistant HIV-1 variants, respectively. Additionally, the molecular docking of 22a with HIV-1 protease provided insight into the ligand-binding properties, which was of great value for further study.

Design, synthesis, and evaluation of novel anti-trypanosomal compounds

Human African trypanosomiasis (HAT) is a deadly neglected tropical disease caused by the protozoan parasite Trypanosoma brucei. During the course of screening a collection of diverse nitrogenous heterocycles, we discovered two novel compounds that contain the tetracyclic core of the Yohimbine and Corynanthe alkaloids, were potent inhibitors of T. brucei proliferation and T. brucei methionyl-tRNA synthetase (TbMetRS) activity. Inspired by these key findings, we prepared several novel series of hydroxyalkyl δ-lactam, δ-lactam, and piperidine analogs and tested their anti-trypanosomal activity. A number of inhibitors were more potent against T. brucei than these initial hits with one hydroxyalkyl δ-lactam derivative being 25-fold more effective in our assay. Surprisingly, most of these active compounds failed to inhibit TbMetRS. This work underscores the importance of verifying, irrespective of close structural similarities, that new compounds designed from a lead with a known biological target engage the putative binding site.

Amino Alcohol Acrylonitriles as Activators of the Aryl Hydrocarbon Receptor Pathway: An Unexpected MTT Phenotypic Screening Outcome.

Lead (Z)-N-(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide, 1 showed MCF-7 GI50 =30 nM and 400-fold selective c.f. MCF10A (normal breast tissue). Acetamide moiety modification (13 a-g) to introduce additional hydrophobicity was favoured with MCF-7 breast cancer cell activity enhanced at 1.3 nM. Other analogues were potent against the HT29 colon cancer cell line at 23 nM. Textbook SAR data was observed in the MCF-7 cell line, in an MTT assay, via the ortho (17 a), meta (17 b) and para (13 f). The amino alcohol -OH moiety was pivotal, but no stereochemical preference noted. But, these data did not fit our homology modelling expectations. Aberrant MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) screening results and metabolic interference confirmed by sulforhodamine B (SRB) screening. Interfering analogues resulted in 120 and 80-fold CYP1A1 and CYP1A2 amplification, with no upregulation of SULT1A1. This is consistent with activation of the AhR pathway. Piperidine per-deuteration reduced metabolic inactivation. 3-OH / 4-OH piperidine analogues showed differential MTT and SRB activity supporting MTT assay metabolic inactivation. Data supports piperidine 3-OH, but not the 4-OH, as a CYP substrate. This family of β-amino alcohol substituted 3,4-dichlorophenylacetonitriles show broad activity modulated via the AhR pathway. By SRB analysis the most potent analogue was 23 b, (Z)-3-(4-(3-(4-phenylpiperidin-1-yl)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile.

Rational Design of Highly Activating Ligands for Cu-Based Atom Transfer Radical Polymerization.

Atom transfer radical polymerization (ATRP) is the most commonly utilized technique in controlled radical polymerization. However, the identification of more active catalysts could further increase its scope, both for polymerization and small-molecule synthesis more generally. To this end, a series of novel ligands were designed on the basis of two strategies: replacing nitrogen-based ligands with their phosphorus equivalents and rigidifying the ligand cap of nitrogen-based ligands so as to enforce short Cu-cap distances. Each ligand was assessed using accurate computational chemistry, which was used to compute the thermodynamics and, in selected cases, kinetics of an ATRP reaction with a model methyl methacrylate propagating radical. In principle, the use of phosphorus ligand caps was found to be a powerful strategy for increasing catalyst activity. Unfortunately, in practice, speciation issues sacrificed much of their advantage. In contrast, cap rigidification increases the activity of nitrogen-based ligands, well beyond existing ATRP ligands such as TPMANMe2. The effectiveness of these ligands was further demonstrated for hard-to-activate initiating systems based on ethylene, vinyl chloride, and vinyl acetate polymerization. Several of these improved ligands are synthetically accessible, with rigid piperidine or quinuclidine analogues of TPMANMe2 possessing improved thermodynamic and kinetic activity by 2 to 3 orders of magnitude.

GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors.

BackgroundThe γ-aminobutyric acid (GABA) transporter GAT1 is involved in GABA transport across the biological membrane in and out of the synaptic cleft. The efficiency of this Na+ coupled GABA transport is regulated by an electrochemical gradient, which is directed inward under normal conditions. However, in certain pathophysiological situations, including strong depolarization or an imbalance in ion homeostasis, the GABA influx into the cytoplasm is increased by re-uptake transport mechanism. This mechanism may lead to extra removal of extracellular GABA which results in numerous neurological disorders such as epilepsy. Thus, small molecule inhibitors of GABA re-uptake may enhance GABA activity at the synaptic clefts.MethodsIn the present study, various GRID-independent molecular descriptor (GRIND) models have been developed to shed light on the 3D structural features of human GAT1 (hGAT1) inhibitors using nipecotic acid and N-diarylalkenyl piperidine analogs. Further, a binding hypothesis has been developed for the selected GAT1 antagonists by molecular docking inside the binding cavity of hGAT1 homology model.ResultsOur results indicate that two hydrogen bond acceptors, one hydrogen bond donor and one hydrophobic region at certain distances from each other play an important role in achieving high inhibitory potency against hGAT1. Our docking results elucidate the importance of the COOH group in hGAT1 antagonists by considering substitution of the COOH group with an isoxazol ring in compound 37, which subsequently leads to a three order of magnitude decrease in biological activity of 37 (IC50 = 38 µM) as compared to compound 1 (IC50 = 0.040 µM).DiscussionOur docking results are strengthened by the structure activity relationship of the data series as well as by GRIND models, thus providing a significant structural basis for understanding the binding of antagonists, which may be useful for guiding the design of hGAT1 inhibitors.