Recognition Mechanism of a Novel Gabapentinoid Drug, Mirogabalin, for Recombinant Human α2δ1, a Voltage-Gated Calcium Channel Subunit.

Mirogabalin is a novel gabapentinoid drug with a hydrophobic bicyclo substituent on the γ-aminobutyric acid moiety that targets the voltage-gated calcium channel subunit α2δ1. Here, to reveal the mirogabalin recognition mechanisms of α2δ1, we present structures of recombinant human α2δ1 with and without mirogabalin analyzed by cryo-electron microscopy. These structures show the binding of mirogabalin to the previously reported gabapentinoid binding site, which is the extracellular dCache_1 domain containing a conserved amino acid binding motif. A slight conformational change occurs around the residues positioned close to the hydrophobic group of mirogabalin. Mutagenesis binding assays identified that residues in the hydrophobic interaction region, in addition to several amino acid binding motif residues around the amino and carboxyl groups of mirogabalin, are critical for mirogabalin binding. The A215L mutation introduced to decrease the hydrophobic pocket volume predictably suppressed mirogabalin binding and promoted the binding of another ligand, L-Leu, with a smaller hydrophobic substituent than mirogabalin. Alterations of residues in the hydrophobic interaction region of α2δ1 to those of the α2δ2, α2δ3, and α2δ4 isoforms, of which α2δ3 and α2δ4 are gabapentin-insensitive, suppressed the binding of mirogabalin. These results support the importance of hydrophobic interactions in α2δ1 ligand recognition.

Gabapentin and intrathecal morphine combination therapy results in decreased oral narcotic use and more consistent pain scores after posterior spinal fusion for adolescent idiopathic scoliosis.

BACKGROUND: Gabapentin and intravenous patient-controlled analgesia (PCA) can reduce postoperative pain scores, postoperative opioid use, and time to completing physical therapy compared to PCA alone after posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS). Gabapentin combined with intrathecal morphine has not been studied. The primary purpose of this retrospective study was to evaluate whether perioperative gabapentin and intrathecal morphine provide more effective pain control than intrathecal morphine alone after PSF for AIS. METHODS: Patients aged 11 to 18 years who underwent PSF for AIS were identified. Patients who received intrathecal morphine only (ITM group) were matched by age and sex to patients who received intrathecal morphine and perioperative gabapentin (ITM+GABA group). The ITM+GABA group received gabapentin preoperatively and for up to 2 days postoperatively. Both groups received oxycodone and the same non-narcotic adjuvant medications. RESULTS: Our final study group consisted of 50 patients (25 ITM, 25 ITM+GABA). The ITM+GABA group had significantly lower mean total oxycodone consumption during the hospitalization (0.798 vs 1.036 mg/kg, P<0.015). While the ITM group had a lower mean pain score between midnight and 8 am on POD 1 (2.4 vs 3.7, P=0.026), pain scores were significantly more consistent throughout the postoperative period in ITM+GABA group. The ITM+GABA group experienced less nausea/vomiting (52% vs 84%, P=0.032) and pruritus (44% vs 72%, P=0.045). Time to physical therapy discharge and length of hospital stay were similar. CONCLUSION: Addition of gabapentin resulted in reduced oral opioid consumption and more consistent postoperative pain scores after PSF for AIS. The patients who received intrathecal morphine and gabapentin also experienced a lower rate of nausea/vomiting and pruritus. TRIAL REGISTRATION: All data was collected retrospectively from chart review, with institutional IRB approval. Trial registration is not applicable.

Development and Validation of 2-Azaspiro [4,5] Decan-3-One (Impurity A) in Gabapentin Determination Method Using qNMR Spectroscopy.

The authors developed a 1H qNMR test procedure for identification and quantification of impurity A present in gabapentin active pharmaceutical ingredient (API) and gabapentin products. The validation studies helped to determine the limit of quantitation and assess linearity, accuracy, repeatability, intermediate precision, specificity, and robustness of the procedure. Spike-and-recovery assays were used to calculate standard deviations, coefficients of variation, confidence intervals, bias, Fisher's F test, and Student's t-test for assay results. The obtained statistical values satisfy the acceptance criteria for the validation parameters. The authors compared the results of impurity A quantification in gabapentin APIs and capsules by using the 1H qNMR and HPLC test methods.

Power function setting in charged aerosol detection for the linearization of detector response - optimization strategies and their application.

Charged aerosol detection (CAD) is an universal technique in liquid chromatography that is increasingly used for the quality control of drugs. Consequently, it has found its way into compendial monographs promoted by its simple and robust application. However, the response of CAD is inherently nonlinear due to its principle of function. Thus, easy and rapid linearization procedures, in particular regarding compendial applications, are highly desirable. One effective approach to linearize the detector's signal makes use of the built-in power function value (PFV) setting of the instrument. The PFV is basically a multiplication factor to the power law exponent of the equation describing the CAD's response, thereby altering the detector's signal output to optimize the quasi-linear range of the response curve. The experimental optimization of the PFV for a series of analytes is a time-consuming process, limiting the practicability of this approach. Here, two independent approaches for the determination of the optimal PFV based on an empirical model and a mathematical transformation in each case, are evaluated. Both approaches can be utilized to predict the optimal PFV for each analyte solely based on the experimental results of a series of calibration standards obtained at a single PFV. The approaches were applied to the HPLC-UV-CAD impurity analysis of the drug gabapentin to improve the observed nonlinear response of the impurities in the range of interest. The predicted optimal PFV of both approaches were in good agreement with the experimentally obtained optimal PFV of the analytes. As a result, the accuracy of the method was significantly improved when using the optimal PFV (90 - 105% versus 81 - 115% recovery rate for quantitation by either single-point calibration or linear regression) for the majority of the analytes. The final method with a PFV adjusted to 1.30 was validated with respect to ICH guideline Q2(R1).

Pre-plasticization of thermal binder facilitates processing and granule growth during melt granulation of gabapentin using co-rotating twin screw extruder.

Plasticization, a common method of reducing the polymer melt viscosity in plastics extrusion, was investigated to improve the processability of a pharmaceutical formulation during twin-screw melt granulation. The thermolabile drug gabapentin was used as a model compound given previous work showed the benefit of preparing 80% drug loading gabapentin granules with hydroxypropyl cellulose as thermal binder. The plasticizer triethyl citrate was selected based on physicochemical compatibility with both the thermal binder and gabapentin by assessing polymer melt rheology and drug stability, respectively. Gabapentin was melt granulated at 80% drug loading with pre-plasticized binder using a co-rotating twin-screw extruder. The chemical stability and tabletability of the pre-plasticized granules were assessed to evaluate granule tabletability, drug stability, and process robustness. The granulation of gabapentin was facilitated by pre-plasticization, showing both increased granule growth and the ability to optimize processing conditions by lowering processing temperature. Pre-plasticization of thermal binder was therefore shown to be beneficial during melt granulation as a method of optimizing processing conditions while maintaining granule robustness.

Liquid chromatography/mass spectrometry analytical determination of gabapentin transformation products by heterogeneous photocatalysis and environmental evaluation.

RATIONALE: Gabapentin is a drug used to treat epilepsy and peripheral neuropathic pain. It is an analog of gamma-aminobutyric acid, and it is a selective blocker of voltage-gated calcium channels. The drug is excreted unmetabolized; it is stable in the environment and is classified as a persistent mobile organic contaminant. Because wastewater treatment plants (WWTPs) are not completely efficient, some bioactive molecules may be released unaltered into the environment. The aim of this study was to provide information about degradation pathways of gabapentin in water by studying its photoinduced transformation products (TPs) through laboratory simulation experiments. Gabapentin and its TPs were monitored in influent and effluent water samples from WWTPs in Germany and Italy. METHODS: The laboratory simulation used heterogeneous photodegradation mediated by titanium dioxide (TiO2 ). Chromatographic separation was achieved using a C18 reverse-phase column, and the structural identification of TPs was performed using high-resolution electrospray ionization high-resolution mass spectrometry (ESI-HRMS) and multistage MSn experiments. RESULTS: Several TPs were observed during TiO2 photodegradation. Nine new compounds were detected, and potential structures were assigned by studying the fragmentation pathways of the [M + H]+ ions of these TPs and gabapentin. Gabapentin and some of the newly identified TPs were found in environmental samples from WWTPs. CONCLUSIONS: The developed high-performance liquid chromatography/high-resolution mass spectrometry method was used to identify TPs from gabapentin. It was then successfully applied to real environmental samples to monitor the TPs as potential environmental pollutants.

Fast simultaneous quantification of gabapentin and cetirizine in cell lysates by means of HPLC-MS/MS.

A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was successfully developed for the simultaneous detection of gabapentin (GBP) and cetirizine (CTZ) in cell lysates. Multiple reaction monitoring (MRM) transitions were found for GBP, CTZ and deuterated internal standards of both, allowing a selective and sensitive detection. Limits of detection (LODs) of 0.04 ng/mL and 0.07 ng/mL were achieved for CTZ and GBP respectively, and a linear range could be confirmed to the highest tested concentration of 50 ng/mL. Furthermore, with a total runtime of 2.5 min, this method allows a high throughput analysis. The applicability of the method was demonstrated by using it for the quantification of CTZ and GBP in cell lysates to examine the effects of renal transporters on these two analytes.

Gabapentin-saccharin co-crystals with enhanced physicochemical properties and in vivo absorption formulated as oro-dispersible tablets.

The physicochemical properties and in vivo absorption of a drug can be altered through cocrystallization with a suitable coformer. The aim of this study was to prepare and characterize Gabapentin (Gaba)-saccharine (sacch) sweet cocrystals for improvement of Gaba physicochemical properties, stability and in vivo absorption in addition to masking its taste. The prepared cocrystals were incorporated into oro-dispersible tablets as an attractive dosage form for pediatrics and adults. Gaba-sacch sweet cocrystals were prepared and characterized using FTIR, DSC, XRD and SEM analysis. They enhanced Gaba solubility and particle size distribution. Oro-dispersible tablets of the sweet cocrystals were prepared and evaluated in comparison to tablets prepared by Gaba-sacch physical mixture (PM). The tablets prepared by the cocrystals had lower wetting and disintegration time with enhanced drug release than those prepared with the physical mixture. The optimized formulation was evaluated for Gaba pharmacokinetics in rabbits in comparison to Gaba-sacch PM tablet and Gaba commercial oral capsules. This formulation had enhanced in vivo drug absorption through significant higher Cmax and AUC0-24 with shorter Tmax. The prepared Gaba-sacch sweet cocrystals oro-dispersible tablets, in addition to its enhanced in vitro and in vivo performance, can also enhance patient compliance through its palatable taste and ease of administration.

Characterization of an Amphetamine Interference from Gabapentin in an LC-HRMS Method.

An amphetamine interference was observed during the development of an liquid chromatography-high-resolution mass spectrometry (LC-HRMS) multi-class confirmation method for the determination of 47 drugs and metabolites in urine. The interference passed all qualitative criteria for amphetamine leading to potential false-positive results. Upon investigation, it was found that the amphetamine interference was correlated with the presence of high levels of gabapentin. Gabapentin is routinely detected in patient urine specimens at levels in excess of 1 mg/mL as it is widely prescribed at high doses and does not undergo significant metabolism. The source of the interference was identified as a gabapentin in-source fragment isomeric with protonated amphetamine. Here we describe the characterization of this interference and how its effect was mitigated in the LC-HRMS method.

Theoretical mechanistic insight into the gabapentin lactamization by an intramolecular attack: Degradation model and stabilization factors.

PURPOSE: Gabapentin is degraded directly into a high toxicity form known as gabapentin lactam (gaba-L) with a maximizing desire in mild pH and low humidity. This study reports the lactamization process of gabapentin, along with a detailed analysis of the energy landscape, geometry, and thermodynamic and kinetic preference of the process. To investigate the effect of the acidic/basic conditions on the energy landscape, the energy profiles were investigated for both protonation and deprotonation forms of gabapentin. METHODS: All the calculations were performed by using the density functional theory (DFT) and the G4MP2 levels of theory in the conductor-like polarizable continuum model, CPCM, and water as the solvent. RESULTS: The lactamization process is an intramolecular cyclization which results in formation of gabapentin-lactam. The chemically intact gabapentin exists in two forms of a stable, R, and a relatively disordered form, R*. The conversion of stable crystalline form R to the intact unstable isomer R* is considered as the primary step in the gabapentin degradation. The results exhibited that near the unstable geometry, R*, a transition state (TS), is 41.3 kcal/mol higher in energy than the optimized ground state, R* (4.1 kcal/mol). From the intrinsic reaction coordinates (IRC) computations, it can be concluded that this transition state led to the unstable R* in one direction and to gabapentin-lactam in the other. CONCLUSIONS: The thermodynamic stability of the lactam form (-13.63 kcal/mol) clarifies the more thermal stability of gaba-L than its related gabapentin form and the experimental preference for the lactamization. The corresponding energy profile on protonation/deprotonation forms of gabapentin indicates the pH-dependent of the process and the rate reduction in out of the mild pH.

Development of Gabapentin Expandable Gastroretentive Controlled Drug Delivery System.

Expandable drug delivery systems are one of many gastroretentive delivery systems which have emerged during the last few years. Expandable systems are usually folded in a capsule and expand to dimensions greater than the pyloric sphincter upon contact with gastric fluid. This prevents them from being evacuated by gastric emptying. The main objective of developing such systems is to increase the residence time of a specific drug in stomach; controlling its release, increasing its bioavailability and decreasing its side effects and dosing frequency. An expandable gastroretentive drug delivery system containing Gabapentin was developed using experimental design (D-optimal reduced quadratic design). This system was able to unfold at stomach pH in less than 15 minutes and obtain a controlled release of 78.1 ± 4.7% in 6 hours following zero-order release kinetic model. It is rigid in stomach and its rigidity decreases at intestinal pH. FTIR analysis indicated the occurrence of hydrogen bonding in Gabapentin when present in the developed system, which might be responsible for the drug's controlled release. XRD analysis indicated that Gabapentin physical properties changed from crystalline in the typical state to amorphous in the developed system.

Advancing synthetic therapies for the treatment of restless legs syndrome.

Introduction: Restless Legs Syndrome/Willis-Ekbom disease (RLS/WED) is a common sensory-motor neurological disorder that impairs nocturnal rest causing decreased alertness, depressed mood, reduced job performance and poor quality of life. In patients affected by moderate to severe RLS/WED, a pharmacological treatment is mandatory. Areas covered: The present review is based on an extensive Internet and PubMed search from 1996 to 2019. It is focused on drugs currently used and under development (phase III and beyond) for the treatment of RLS/WED. Expert opinion: The drugs currently available for the treatment of the disease do not always allow for obtaining the optimal control of symptoms, in particular in the long-term treatment. Although initially effective, long-term dopaminergic treatment tends to wane over time and augmentation can occur. Updated international guidelines now recommend α2δ calcium channel ligand medications as the initial drug of choice. Oxycodone-naloxone demonstrated a significant and sustained treatment effect for patients with severe RLS/WED insufficiently controlled with previous treatments. Head-to-head trials of different drugs, as well as more studies on nondopaminergic agents and combination therapy, are greatly needed. Monoamine oxidase B inhibitors could be good candidates for the initial treatment of RLS/WED, sparing stronger dopaminergic agents for later stages of the disease.

Compounded gabapentin for neuropathic pain: Stability and beyond-use date (BUD) in some commonly used bases.

OBJECTIVES: To investigate the stability and beyond-use date (BUD) of topical gabapentin in 3 commonly used bases. METHODS: Lipoderm cream, Versabase gel, and Emollient cream were used to compound gabapentin (10%). The products were stored in Ecolojars, kept at 25°C, 4°C, and 40°C, and samples were collected on different days (days 0, 14, 28, and 90). Potency, stability, and organoleptic changes were monitored. RESULTS: At 25°C and 40°C, the potency of gabapentin in Lipoderm cream significantly increased (P < 0.05) after 28 and 90 days, respectively. In contrast, gabapentin degraded in Emollient cream (P < 0.05). At 25°C, the organoleptic properties of the drug compounded with Lipoderm cream (25°C) remained consistent for up to 28 days but showed signs of physical changes in other bases. Gabapentin recrystallized from Versabase gel and Emollient cream within 14 days. CONCLUSION: Gabapentin compounded with Lipoderm cream for topical use was stable in Ecolojars for 28 days at 25°C. Under the same conditions, the drug was not stable in Versabase gel and Emollient cream. Based on our stability and potency data, the beyond-use date of currently dispensed gabapentin (10%) formulations with Lipoderm cream should not be extended beyond the currently assigned 30-day mark, even when refrigerated. It is unclear whether the stability of these formulations is improved if stored in air-tight containers.

Effect of screw profile and processing conditions on physical transformation and chemical degradation of gabapentin during twin-screw melt granulation.

Twin-screw melt granulation (TSMG) was applied to process a powder blend consisting of 80% gabapentin (GABA) and 20% hydroxypropyl cellulose. The effect of screw profile and processing conditions on the process-induced transformation and chemical degradation of gabapentin was studied. When a neutral kneading block was used, gabapentin underwent polymorphic transformation. A forward kneading block in combination with processing under torque conditions was required to minimize chemical degradation and to inhibit polymorphic transformation of gabapentin. Both the size of the extruded granules and gabapentin degradant level correlated positively with the specific rate, the ratio between feed rate and screw speed. At higher specific rate, the barrel was filled to a greater extent. The material packing and compressive forces were enhanced, as proven by the increased rupturing of CAMES® sensor beads and GABA crystal size reduction. This resulted in more interaction between the powder particles and facilitated granule growth. Simultaneously, this also resulted in higher degradant level. To attain adequate tabletability, the specific rate must reach a threshold value. The development of an optimum TSMG process requires balancing processing parameters based on the physical and chemical stability of GABA as well as its tabletability.

Investigating the Mechanism of L-Valine in Improving the Stability of Gabapentin Combining Chemical Analysis Experiments with Computational Pharmacy.

The mechanism of L-Val on how to improve the stability of gabapentin (GBP) was described by the combination of chemical analysis experiments and computer simulations. Scanning electron microscope (SEM), powder X-ray diffraction (PXRD), and differential scanning calorimeter (DSC), coupled with attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), were used to identify ß-GBP prepared by rapid solvent removal method. The reaction barriers on crystal planes, ß-GBP (100) and ß-GBP (10-1), are smaller than α-GBP and γ-GBP, reaching 276.65 kJ/mol and 299.57 kJ/mol, respectively. Thus, it was easier for ß-GBP to form lactam, and the occurrence of ß-GBP would lead the worse stability of α-GBP. The addition of neutral amino acids such as L-Val could improve the stability of α-GBP effectively. The adsorption energy of α-GBP (002) crystal plane with L-Val is larger than that of other crystal planes, reaching 42.17 kJ/mol. Hydrogen bond was the combination of L-Val and GBP main crystal planes, which could inhibit the crystal transformation of α-GBP. These results suggest that neutral amino acid protectants, such as L-Val, could improve the stability of α-GBP effectively, and inhibition of crystal transformation is one of the effective methods to improve the stability of polymorphic drugs.

Effects of thermal binders on chemical stabilities and tabletability of gabapentin granules prepared by twin-screw melt granulation.

The effect of thermal binders on the physicochemical properties of gabapentin, a thermally labile drug, in granules prepared using twin-screw melt granulation was investigated in this study. Hydroxypropyl cellulose (HPC), a thermoplastic high molecular-weight binder, was compared against conventional low molecular-weight semi-crystalline thermal binders PEG 8000 and Compritol. Both the chemical degradation and polymorph form change of gabapentin were analyzed. The effects of particle size and molecular weight of HPC on the properties of granules were also studied. To overcome the high melt viscosity of HPC, higher barrel temperatures and higher specific mechanical energy were required to attain suitable granules. As a result, higher levels of gabapentin degradant were observed in HPC-based formulations. However, gabapentin form change was not observed in all formulations. Smaller particle size and lower molecular weight of HPC led to faster granule growth. The tabletability of granules was insensitive to the variations in particle size and molecular weight of HPC. Gabapentin crystal size reduction, HPC size reduction, and HPC enrichment on granule surface were observed for HPC-based granules.

Evidence of human-like Ca2+ channels and effects of Ca2+ channel blockers in Acanthamoeba castellanii.

The evolution of voltage-gated calcium channel (Cav) in eukaryotes is an area of interest for biologists worldwide. The CLAN CL0030 and its family Ion_Trans 2 PF 07885 have been known to be present in prokaryotes, but the origin of these ion channels in Acanthamoeba spp. is yet to be determined. We inferred the origin of primitive forms of two-pore channels like proteins, human-like Cav 1.1 of L-type, and Cav subunit alpha-2/delta-1 in Acanthamoeba spp. early during evolution. By in-depth investigation into genomics, transcriptomics, use of bioinformatics tools and experimentations done with drugs like amlodipine and gabapentin on Acanthamoeba spp., we show the evidence of primitive forms of these channels in this protist pathogen. Genomics and transcriptomics of proteins ACA1_167020, 092610, and 270170 reflected their cellular expression in Acanthamoeba spp. We performed amino acid sequence homology, 3D structural modeling, ligand binding predictions, and dockings. Bioinformatics and 3D structural models show similarities between ACA1_167020, 092610, 270170, and different types of known human Cav. We show amoebicidal effects of amlodipine and gabapentin on Acanthamoeba spp., which can help design their structural analogs to target pathogenic genotypes of Acanthamoeba in diseases like Acanthamoeba keratitis and granulomatous amoebic encephalitis.

Gabapentin in Elastic Liposomes: Preparation, Characterization, Drug Release, and Penetration Through Porcine Skin.

In the outpatient pharmacy compounding, gabapentin, an anti-epileptic agent, has been commonly prescribed to be prepared alone or in combination with other agents in Pluronic lecithin organogel for transdermal pain management and palliative care. The objective of this study was to formulate and characterize gabapentin encapsulated elastic liposomes and then compare the gabapentin-based liposomes with compounded gabapentin-based Pluronic lecithin organogel regarding their efficiency in transdermal delivery of gabapentin. We demonstrated that our small 100-nm unilamellar vesicles of gabapentin encapsulated approximately 6.9 mg/mL Å} 0.2 mg/mL with up to 70% of encapsulation efficiency. Gabapentin released slowly from liposomes over 12 hours while it rapidly released from Pluronic lecithin organogel within 4 hours. We also showed that after 24 hours liposomes significantly accelerated the percutaneous penetration of gabapentin through the porcine skin leading to higher cumulative drug concentrations (~98% of drug permeated with a mean flux of 188.94 µg/cm2/h Å} 42.16 µg/cm2/h) as compared to Pluronic lecithin organogel (~55 % of drug permeated with a mean flux of 56.32 µg/cm2/h Å} 41.93 µg/cm2/h). In conclusion, the elastic liposomal formulation showed higher efficiency than the compounded Pluronic lecithin organogel in the transdermal delivery of gabapentin through porcine skin.

Using Manufacturing Design Space Concepts for Stability Risk Assessment-Gabapentin NIPTE/FDA Case Study.

A quantitative, model-based risk assessment process was evaluated using Bayesian parameter estimation to determine the posterior distribution of the probability of a model tablet formulation's (gabapentin) ability to meet end-of-expiry stability criteria-based manufacturing controls. Experimental data was obtained from an FDA-supported, multi-year project that involved researchers at nine universities working collaboratively with industrial and governmental scientists under the leadership of the National Institute for Pharmaceutical Technology and Education (NITPE). The risk assessment process involved the development of a design space manufacturing model and shelf life stability model that shared stability-related critical quality attributes (CQAs). Monte Carlo simulations of the design space and shelf life models that uses model parameter uncertainty to estimate the probability of shelf life failure as a function of manufacturing control. The resultant linked design space and shelf life stability models were tested by comparing model predicted and observed long-term stability data generated under a variety of pilot scale production conditions.

Pushing the Limits of Computational Structure-Based Drug Design with a Cryo-EM Structure: The Ca2+ Channel α2δ-1 Subunit as a Test Case.

Cryo-electron microscopy (cryo-EM) is emerging as a real alternative for structural elucidation. In spite of this, very few cryo-EM structures have been described so far as successful platforms for in silico drug design. Gabapentin and pregabalin are some of the most successful drugs in the treatment of epilepsy and neuropathic pain. Although both are in clinical use and are known to exert their effects by binding to the regulatory α2δ subunit of voltage gated calcium channels, their binding modes have never been characterized. We describe here the successful use of an exhaustive protein-ligand sampling algorithm on the α2δ-1 subunit of the recently published cryo-EM structure, with the goal of characterizing the ligand entry path and binding mode for gabapentin, pregabalin, and several other amino acidic α2δ-1 ligands. Our studies indicate that (i) all simulated drugs explore the same path for accessing the occluded binding site on the interior of the α2δ-1 subunit; (ii) they all roughly occupy the same pocket; (iii) the plasticity of the binding site allows the accommodation of a variety of amino acidic modulators, driven by the flexible "capping loop" delineated by residues Tyr426-Val435 and the floppy nature of Arg217; (iv) the predicted binding modes are in line with previously available mutagenesis data, confirming Arg217 as key for binding, with Asp428 and Asp467 highlighted as additional anchoring points for all amino acidic drugs. The study is one of the first proofs that latest-generation cryo-EM structures combined with exhaustive computational methods can be exploited in early drug discovery.