Amino Acids as the Potential Co-Former for Co-Crystal Development: A Review

Co-crystals are one of the most popular ways to modify the physicochemical properties of active pharmaceutical ingredients (API) without changing pharmacological activity through non-covalent interactions with one or more co-formers. A “green method” has recently prompted many researchers to develop solvent-free techniques or minimize solvents for arranging the eco-friendlier process of co-crystallization. Researchers have also been looking for less-risk co-formers that produce the desired API’s physicochemical properties. This review purposed to collect the report studies of amino acids as the safe co-former and explored their advantages. Structurally, amino acids are promising co-former candidates as they have functional groups that can form hydrogen bonds and increase stability through zwitterionic moieties, which support strong interactions. The co-crystals and deep eutectic solvent yielded from this natural compound have been proven to improve pharmaceutical performance. For example, l-glutamine could reduce the side effects of mesalamine through an acid-base stabilizing effect in the gastrointestinal fluid. In addition, some amino acids, especially l-proline, enhances API’s solubility and absorption in its natural deep eutectic solvent and co-crystals systems. Moreover, some ionic co-crystals of amino acids have also been designed to increase chiral resolution. Therefore, amino acids are safe potential co-formers, which are suitable for improving the physicochemical properties of API and prospective to be developed further in the dosage formula and solid-state syntheses.     

Evaluating hydrogen-bond propensity,hydrogen-bond coordination and hydrogen-bond energy as tools for predicting the outcome of attempted co-crystallisations

ABSTRACT

Two different structure-informatics based methods and one approach based on hydrogen-bond interaction energies were evaluated for their abilities to predict the experimental outcomes of attempted co-crystallisations between two known drug molecules, Nevirapine and Diclofenac, and a series of potential co-formers. The hydrogen-bond propensity (HBP) tool gave the correct result in 26 out of 30 cases, whereas a hydrogen-bond coordination (HBC) method predicted the correct outcome in 22 out of 30 cases. Finally, calculated hydrogen-bond energies (HBE) using a simple electrostatic model, gave the correct result in 23 out of 30 experiments. In those cases, where the crystal structure of a co-crystal of either Nevirapine or Diclofenac was known, we also examined how well the three methods predicted which primary hydrogen-bond interactions were present in the crystal structure. HBP correctly predicted 6 out of 6 cases, HBC could not predict any of the synthon formations correctly, and HBE successfully predicted 1 out of 6 cases.     

Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening

In this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for 2,4-diaminopyrimidine (DAP), which is the pharmacophore of these active pharmaceutical ingredients (API). The isomeric pyridinecarboxamides and two xanthines, theophylline (THEO) and caffeine (CAF), were used as co-formers in the same experimental conditions, in order to evaluate the potential for the pharmacophore to be used as a guide in the screening process. In silico co-crystal screening was carried out using BIOVIA COSMOquick and experimental screening was performed by mechanochemistry and supported by (solid + liquid) binary phase diagrams, infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). The in silico prediction of low propensities for DAP, TMP and PMA to co-crystallize with pyridinecarboxamides was confirmed: a successful outcome was only observed for DAP + nicotinamide. Successful synthesis of multicomponent solid forms was achieved for all three target molecules with theophylline, with DAP co-crystals revealing a greater variety of stoichiometries. The crystalline structures of a (1:2) TMP:THEO co-crystal and of a (1:2:1) DAP:THEO:ethyl acetate solvate were solved. This work demonstrated the possible use of the pharmacophore of DHFR inhibitors as a guide for co-crystal screening, recognizing some similar trends in the outcome of association in the solid state and in the molecular aggregation in the co-crystals, characterized by the same supramolecular synthons.     

Energetic Co-Crystal of a Primary Metal-Free Explosive with BTF. Ideal Pair for Co-Crystallization

Co-crystallization is an elegant technique to tune the physical properties of crystalline solids. In the field of energetic materials, co-crystallization is currently playing an important role in the engineering of crystals with improved performance. Here, based on an analysis of the structural features of the green primary explosive, tetramethylammonium salt of 7-oxo-5-(trinitromethyl)-4,5,6,7-tetrahydrotetrazolo[1,5-a][1,3,5]triazin-5-ide (1), a co-former such as the powerful secondary explosive, benzotrifuroxan (BTF, 2), has been proposed to improve it. Compared to the original 1, its co-crystal with BTF has a higher detonation pressure and velocity, as well as an initiating ability, while the impact sensitivity and thermal stability remained at about the same level. Both co-formers, 1 and 2, and co-crystal 3 were characterized by single-crystal X-ray diffraction and their crystal packing was analyzed in detail by the set of approaches, including periodic calculations. In the co-crystal 3, all intermolecular interactions were significantly redistributed. However, no new types of intermolecular interactions were formed during co-crystallization. Moreover, the interaction energies of structural units in crystals before and after co-crystallization were approximately the same. A similar trend was observed for the volumes occupied by structural units and their densifications. The similar nature of the organization of the crystals of the co-formers and the co-crystal gives grounds to assert that the selected co-formers are an ideal pair for co-crystallization, and the invariability of the organization of the crystals was probably responsible for the preservation of some of their properties.     

Resolution of Halogenated Mandelic Acids through Enantiospecific Co-Crystallization with Levetiracetam

The resolution of halogenated mandelic acids using levetiracetam (LEV) as a resolving agent via forming enantiospecific co-crystal was presented. Five halogenated mandelic acids, 2-chloromandelic acid (2-ClMA), 3-chloromandelic acid (3-ClMA), 4-chloromandelic acid (4-ClMA), 4-bromomandelic acid (4-BrMA), and 4-fluoromandelic acid (4-FMA), were selected as racemic compounds. The effects of the equilibrium time, molar ratio of the resolving agent to racemate, amount of solvent, and crystallization temperature on resolution performance were investigated. Under the optimal conditions, the resolution efficiency reached up to 94% and the enantiomeric excess (%e.e.) of (R)-3-chloromandelic acid was 63%e.e. All five halogenated mandelic acids of interest in this study can be successfully separated by LEV via forming enantiospecific co-crystal, but the resolution performance is significantly different. The results showed that LEV selectively co-crystallized with S enantiomers of 2-ClMA, 3-ClMA, 4-ClMA, and 4-BrMA, while it co-crystallized with R enantiomers of 4-FMA. This indicates that the position and type of substituents of racemic compounds not only affect the co-crystal configuration, but also greatly affect the efficiency of co-crystal resolution.     

环四甲撑四硝胺/1,3,5-三氨基-2,4,6-三硝基苯共晶炸药的分子模拟研究

构建环四甲撑四硝胺 (HMX) /1,3,5-三氨基-2,4,6三硝基苯 (TATB)不同的共晶结构模型,用分子动力学(MD)模拟得到其平衡结构。基于平衡结构进行X射线粉末衍射（XRD）图谱模拟和能量计算。结果表明,与纯组分相比,HMX/TATB共晶结构的X射线粉末衍射图与主成分HMX相似,并均有新峰出现;TATB在HMX表面自由能最高、生长速率最慢的 (0 1 1) 晶面上发生取代后的能量最低,结构最稳定,据此推测在制备HMX/TATB共晶炸药过程中,TATB分子更容易进入HMX自由能高的晶面,得到结构稳定的共晶而使HMX变得更为钝感。     

The Use of Bovine Serum Albumin as a Ligand in Affinity Chromatographic Clean-up of Non-Steroidal Anti-Inflammatory Drugs from Bovine Plasma

The European Union regulates the use of non-steroidal anti-inflammatory drugs (NSAID) in animal production and official national analytical monitoring programmes have been set up in each member state to detect residues of the drugs in bovine plasma. In this work, we describe the development and application of affinity chromatography for molecular recognition of NSAID in bovine plasma. Bovine serum albumin (BSA), the plasma protein which binds such drugs, was covalently bound to a polymeric support via its glycosyl moieties. Loading capacities and specificity were tested both on standard solutions and on spiked bovine plasma for nine drugs—ketoprofen, naproxen, phenylbutazone, oxyphenylbutazone, acetylsalicylic acid, salicylic acid, tolfenamic acid, diclofenac, and nimesulide—chosen as being the most representative of the different chemical sub-classes of NSAID. The BSA columns could bind up to 150 × 10^–6 g total of a mixture of these nine NSAID, with mean recoveries ranging from 74.0% (tolfenamic acid) to 96.0% (nimesulide). HPLC separation on an RP C₁₈ column with a linear gradient enabled resolution of the drugs; identification was achieved by coupling with photodiode array detection (DAD) operated at 240 and 280 nm. Results showed that all the compounds except acetylsalicylic acid were bound effectively by the BSA affinity columns. When plasma samples were spiked at 2.5 g mL^–1 with a mixture of the NSAID the chromatographic profile and UV spectra recorded (in the range 220–350 nm) indicated the procedure was sufficiently selective for identification of the drugs at the concentrations expected according to their pharmacokinetics. No memory effects and matrix interferences were observed.Revised: 18 December 2003 and 16 April 2004     

Natural Product-Based Hybrids as Potential Candidates for the Treatment of Cancer: Focus on Curcumin and Resveratrol

One of the main current strategies for cancer treatment is represented by combination chemotherapy. More recently, this strategy shifted to the “hybrid strategy”, namely the designing of a new molecular entity containing two or more biologically active molecules and having superior features compared with the individual components. Moreover, the term “hybrid” has further extended to innovative drug delivery systems based on biocompatible nanomaterials and able to deliver one or more drugs to specific tissues or cells. At the same time, there is an increased interest in plant-derived polyphenols used as antitumoral drugs. The present review reports the most recent and intriguing research advances in the development of hybrids based on the polyphenols curcumin and resveratrol, which are known to act as multifunctional agents. We focused on two issues that are particularly interesting for the innovative chemical strategy involved in their development. On one hand, the pharmacophoric groups of these compounds have been used for the synthesis of new hybrid molecules. On the other hand, these polyphenols have been introduced into hybrid nanomaterials based on gold nanoparticles, which have many potential applications for both drug delivery and theranostics in chemotherapy.     

Plant Secondary Metabolites Produced in Response to Abiotic Stresses Has Potential Application in Pharmaceutical Product Development

Plant secondary metabolites (PSMs) are vital for human health and constitute the skeletal framework of many pharmaceutical drugs. Indeed, more than 25% of the existing drugs belong to PSMs. One of the continuing challenges for drug discovery and pharmaceutical industries is gaining access to natural products, including medicinal plants. This bottleneck is heightened for endangered species prohibited for large sample collection, even if they show biological hits. While cultivating the pharmaceutically interesting plant species may be a solution, it is not always possible to grow the organism outside its natural habitat. Plants affected by abiotic stress present a potential alternative source for drug discovery. In order to overcome abiotic environmental stressors, plants may mount a defense response by producing a diversity of PSMs to avoid cells and tissue damage. Plants either synthesize new chemicals or increase the concentration (in most instances) of existing chemicals, including the prominent bioactive lead compounds morphine, camptothecin, catharanthine, epicatechin-3-gallate (EGCG), quercetin, resveratrol, and kaempferol. Most PSMs produced under various abiotic stress conditions are plant defense chemicals and are functionally anti-inflammatory and antioxidative. The major PSM groups are terpenoids, followed by alkaloids and phenolic compounds. We have searched the literature on plants affected by abiotic stress (primarily studied in the simulated growth conditions) and their PSMs (including pharmacological activities) from PubMed, Scopus, MEDLINE Ovid, Google Scholar, Databases, and journal websites. We used search keywords: “stress-affected plants,” “plant secondary metabolites, “abiotic stress,” “climatic influence,” “pharmacological activities,” “bioactive compounds,” “drug discovery,” and “medicinal plants” and retrieved published literature between 1973 to 2021. This review provides an overview of variation in bioactive phytochemical production in plants under various abiotic stress and their potential in the biodiscovery of therapeutic drugs. We excluded studies on the effects of biotic stress on PSMs.     

Synthesis and Neurotropic Activity of New Heterocyclic Systems: Pyridofuro[3,2-d]pyrrolo[1,2-a]pyrimidines,Pyridofuro[3,2-d]pyrido[1,2-a]pyrimidines and Pyridofuro[3′,2′:4,5]pyrimido[1,2-a]azepines

Background: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. Objective: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. Methods: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. Results: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of “open field” and “elevated plus maze” (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of “forced swimming” (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABA_A receptor with a value of the scoring function that estimates free energy of binding (ΔG) at −7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT_1A receptor. Conclusions: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.     

定常冲击波作用下六硝基六氮杂异伍兹烷(CL-20)/奥克托今(HMX)含能共晶初始分解机理研究

采用ReaxFF分子动力学方法同时结合多尺度冲击技术(MSST)模拟了4–10 km×s~(-1)定常冲击波加载下含能共晶CL-20/HMX沿不同晶格矢量的初始物理化学响应。获得了系统温度、压力、密度以及粒子速度的时间演化路径,以及初始分解路径,最终稳定反应产物和冲击雨贡纽等。研究结果表明:冲击波入射至含能共晶后,物理上依次经历诱导期、快压缩、慢压缩以及膨胀过程。快压缩和慢压缩过程分别对应反应物的快分解和慢分解。采用指数函数对反应物的衰减曲线进行拟合,并比较了共晶中反应物的衰减速率。整体上,随着冲击波速度的增加,反应物响应的时间逐渐提前,并且,冲击波沿各晶格矢量入射后,共晶中CL-20分子分解的响应时间均早于HMX。CL-20快分解阶段的衰减速率最高,HMX快分解的衰减速率居其次。相对于快分解阶段,慢分解阶段各反应物的衰减速率差异较小。含能共晶的初始反应路径是CL-20聚合形成二聚体,而冲击诱导共晶分解的初始反应路径是CL-20中N-NO_2键断裂形成NO_2。随后产生N_2O,NO,HONO,OH,H等中间小分子。最终稳定产物是N_2,H_2O,CO_2,CO和H_2。晶格矢量b,c方向冲击感度相同,低于晶格矢量a方向的感度。冲击诱导共晶中CL-20和HMX分解的最小冲击波速度(us)分别为6 km×s~(-1)和7 km×s~(-1)。采用冲击雨贡纽关系计算得到沿晶格矢量a,b,c冲击诱导CL-20/HMX共晶起爆的压力分别为16.52 GPa,17.41 GPa和17.41 GPa。爆轰压力范围介于36.75 GPa–47.43 GPa。     

A Rationale for Drug Design Provided by Co-Crystal Structure of IC261 in Complex with Tubulin

Microtubules composed of α/β tubulin heterodimers are an essential part of the cytoskeleton of eukaryotic cells and are widely regarded as targets for cancer chemotherapy. IC261, which is discovered as an ATP-competitive inhibitor of serine/threonine-specific casein kinase 1 (CK1), has shown its inhibitory activity on microtubule polymerization in recent studies. However, the structural information of the interaction between tubulin and IC261 is still unclear. Here, we provided a high-resolution (2.85 Å) crystal structure of tubulin and IC261 complex, revealed the intermolecular interaction between tubulin and IC261, and analyzed the structure–activity relationship (SAR). Subsequently, the structure of tubulin-IC261 complex was compared with tubulin-colchicine complex to further elucidate the novelty of IC261. Furthermore, eight optimal candidate compounds of new IC261-based microtubule inhibitors were obtained through molecular docking studies. In conclusion, the co-crystal structure of tubulin-IC261 complex paves a way for the design and development of microtubule inhibitor drugs.     

RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays

RNA splicing is an essential step in producing mature messenger RNA (mRNA) and other RNA species. Harnessing RNA splicing modifiers as a new pharmacological modality is promising for the treatment of diseases caused by aberrant splicing. This drug modality can be used for infectious diseases by disrupting the splicing of essential pathogenic genes. Several antisense oligonucleotide splicing modifiers were approved by the U.S. Food and Drug Administration (FDA) for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Recently, a small-molecule splicing modifier, risdiplam, was also approved for the treatment of SMA, highlighting small molecules as important warheads in the arsenal for regulating RNA splicing. The cellular targets of these approved drugs are all mRNA precursors (pre-mRNAs) in human cells. The development of novel RNA-targeting splicing modifiers can not only expand the scope of drug targets to include many previously considered “undruggable” genes but also enrich the chemical-genetic toolbox for basic biomedical research. In this review, we summarized known splicing modifiers, screening methods for novel splicing modifiers, and the chemical space occupied by the small-molecule splicing modifiers.     

飞秒激光烧蚀含能材料的分子动力学模拟

为了得到飞秒激光侵蚀(FLA)1, 3二硝基甲苯(简称DNB,分子式：C₆H₄N₂O₄),六硝基六氮杂异伍兹烷(简称CL20,分子式：C₆H₆N₁₂O₁₂)和CL20/DNB共晶系统的物理和化学响应过程,本文采用ReaxFF/lg反应力场对其过程进行模拟。计算结果表明,CL20/DNB系统的温度和压力在飞秒激光加载过程中出现阶跃,激光加载过程后系统有一个冷却过程,然后系统的温度和压力逐渐升高达到最大值并维持平衡。研究发现,在此过程中CL20和CL20/DNB系统触发反应均为CL20分子中的N―NO₂断裂。CL20系统的分解速率大于CL20/DNB共晶系统,这可能是因为共晶系统在反应初期具有大量的DNB分子以及分解产物中含有比较稳定的苯环减少了CL20及其产物之间的有效碰撞。     

Molecular Dynamics Simulations for Effects of Fluoropolymer Binder Content in CL-20/TNT Based Polymer-Bonded Explosives

In order to better understand the role of binder content, molecular dynamics (MD) simulations were performed to study the interfacial interactions, sensitivity and mechanical properties of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane/2,4,6-trinitrotoluene (CL-20/TNT) based polymer-bonded explosives (PBXs) with fluorine rubber F₂₃₁₁. The binding energy between CL-20/TNT co-crystal (1 0 0) surface and F₂₃₁₁, pair correlation function, the maximum bond length of the N–NO₂ trigger bond, and the mechanical properties of the PBXs were reported. From the calculated binding energy, it was found that binding energy increases with increasing F₂₃₁₁ content. Additionally, according to the results of pair correlation function, it turns out that H–O hydrogen bonds and H–F hydrogen bonds exist between F₂₃₁₁ molecules and the molecules in CL-20/TNT. The length of trigger bond in CL-20/TNT were adopted as theoretical criterion of sensitivity. The maximum bond length of the N–NO₂ trigger bond decreased very significantly when the F₂₃₁₁ content increased from 0 to 9.2%. This indicated increasing F₂₃₁₁ content can reduce sensitivity and improve thermal stability. However, the maximum bond length of the N–NO₂ trigger bond remained essentially unchanged when the F₂₃₁₁ content was further increased. Additionally, the calculated mechanical data indicated that with the increase in F₂₃₁₁ content, the rigidity of CL-20/TNT based PBXs was decrease, the toughness was improved.     

A Multi-Objective Approach for Drug Repurposing in Preeclampsia

Preeclampsia is a hypertensive disorder that occurs during pregnancy. It is a complex disease with unknown pathogenesis and the leading cause of fetal and maternal mortality during pregnancy. Using all drugs currently under clinical trial for preeclampsia, we extracted all their possible targets from the DrugBank and ChEMBL databases and labeled them as “targets”. The proteins labeled as “off-targets” were extracted in the same way but while taking all antihypertensive drugs which are inhibitors of ACE and/or angiotensin receptor antagonist as query molecules. Classification models were obtained for each of the 55 total proteins (45 targets and 10 off-targets) using the TPOT pipeline optimization tool. The average accuracy of the models in predicting the external dataset for targets and off-targets was 0.830 and 0.850, respectively. The combinations of models maximizing their virtual screening performance were explored by combining the desirability function and genetic algorithms. The virtual screening performance metrics for the best model were: the Boltzmann-Enhanced Discrimination of ROC (BEDROC)_α=160.9 = 0.258, the Enrichment Factor (EF)_1% = 31.55 and the Area Under the Accumulation Curve (AUAC) = 0.831. The most relevant targets for preeclampsia were: AR, VDR, SLC6A2, NOS3 and CHRM4, while ABCG2, ERBB2, CES1 and REN led to the most relevant off-targets. A virtual screening of the DrugBank database identified estradiol, estriol, vitamins E and D, lynestrenol, mifrepristone, simvastatin, ambroxol, and some antibiotics and antiparasitics as drugs with potential application in the treatment of preeclampsia.