RESUMEN
The HIV-1 envelope glycoprotein (Env) trimer mediates cell entry and is conformationally dynamic1-8. Imaging by single-molecule fluorescence resonance energy transfer (smFRET) has revealed that, on the surface of intact virions, mature pre-fusion Env transitions from a pre-triggered conformation (state 1) through a default intermediate conformation (state 2) to a conformation in which it is bound to three CD4 receptor molecules (state 3)8-10. It is currently unclear how these states relate to known structures. Breakthroughs in the structural characterization of the HIV-1 Env trimer have previously been achieved by generating soluble and proteolytically cleaved trimers of gp140 Env that are stabilized by a disulfide bond, an isoleucine-to-proline substitution at residue 559 and a truncation at residue 664 (SOSIP.664 trimers)5,11-18. Cryo-electron microscopy studies have been performed with C-terminally truncated Env of the HIV-1JR-FL strain in complex with the antibody PGT15119. Both approaches have revealed similar structures for Env. Although these structures have been presumed to represent the pre-triggered state 1 of HIV-1 Env, this hypothesis has never directly been tested. Here we use smFRET to compare the conformational states of Env trimers used for structural studies with native Env on intact virus. We find that the constructs upon which extant high-resolution structures are based predominantly occupy downstream conformations that represent states 2 and 3. Therefore, the structure of the pre-triggered state-1 conformation of viral Env that has been identified by smFRET and that is preferentially stabilized by many broadly neutralizing antibodies-and thus of interest for the design of immunogens-remains unknown.
Asunto(s)
Transferencia Resonante de Energía de Fluorescencia , VIH-1/química , Imagen Individual de Molécula , Productos del Gen env del Virus de la Inmunodeficiencia Humana/química , Animales , Anticuerpos Neutralizantes/inmunología , Bovinos , Disulfuros/química , Células HEK293 , VIH-1/genética , VIH-1/inmunología , Humanos , Modelos Moleculares , Mutación , Conformación Proteica , Multimerización de Proteína , Estabilidad Proteica , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
The construction of a chemical library based on natural products is a promising method for the synthesis of natural product-like compounds. In this study, we synthesized a terpenoid alkaloid-like compound library based on the humulene skeleton. Our strategy, which enables access to diverse ring systems such as 11-membered monocyclic, oxabicyclic, and medium-sized aza ring-containing scaffolds, involves the introduction of a nitrogen atom, an intermolecular C-O bond formation via Lewis acid-mediated epoxide-opening transannulation, and a ring-reconstruction strategy based on olefin metathesis. A cheminformatics analysis based on their structural and physicochemical properties revealed that the synthesized compounds have high three-dimensionality and high natural product likeness scores but with structural novelty. The usefulness of the terpenoid alkaloid-like compound library for drug discovery and the accessibility to structure-activity relationship studies were validated by performing an assay for osteoclast-specific tartrate-resistant acid phosphatase activity, resulting in the identification of a seed compound for bone-resorptive diseases such as osteoporosis.
Asunto(s)
Alcaloides , Sesquiterpenos Monocíclicos , Alcaloides/química , Alcaloides/síntesis química , Sesquiterpenos Monocíclicos/química , Relación Estructura-Actividad , Terpenos/química , Terpenos/síntesis química , Productos Biológicos/química , Productos Biológicos/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Sesquiterpenos/química , Sesquiterpenos/síntesis químicaRESUMEN
Labdane-related diterpenoids (LRDs) in fungi are a pharmaceutically important, but underexplored family of natural products. In the biosynthesis of fungal LRDs, bifunctional terpene cyclases (TCs) consisting of αßγ domains are generally used to synthesize the polycyclic skeletones of LRDs. Herein, we conducted genome mining of LRDs in our fungal genome database and identified a unique pair of TCs, AsPS and AsCPS, in the fungus Arthrinium sacchari. AsPS consists of catalytically active α and inactive ß domains, whereas AsCPS contains ßγ domains and a truncated α domain. Heterologous expression in Aspergillus oryzae and biochemical characterization of recombinant proteins demonstrated that AsCPS synthesized copalyl diphosphate and that AsPS then converted it to (-)-sandaracopimaradiene. Since AsPS and AsCPS have distinct domain organizations from those of known fungal TCs and are likely generated through fusion or loss of catalytic domains, our findings provide insight into the evolution of TCs in fungi.
RESUMEN
By mining fungal genomic information, a noncanonical iterative type I PKS fused with an N-terminal adenylation-thiolation didomain, which catalyzes the formation of naringenin chalcone, was found. Structural prediction and molecular docking analysis indicated that a C-terminal thioesterase domain was involved in the Claisen-type cyclization. An enzyme responsible for formation of (2S)-flavanone in the biosynthesis of fungal flavonoids was also identified. Collectively, these findings demonstrate unprecedented fungal biosynthetic machinery leading to plant-like metabolites.
Asunto(s)
Aciltransferasas , Flavonoides , Simulación del Acoplamiento Molecular , Flavonoides/químicaRESUMEN
This article describes the first total synthesis of luminamicin using a strategy combining chemical degradation with synthesis. Chemical degradation studies provided a sense of the inherent reactivity of the natural product, and deconstruction of the molecule gave rise to a key intermediate, which became the target for chemical synthesis. The core structure of the southern part of luminamicin was constructed by a 1,6-oxa-Michael reaction to form an oxa-bridged ring, followed by coupling with a functionalized organolithium species. Modified Shiina macrolactonization conditions forged the strained 10-membered lactone containing a tri-substituted olefin. Diastereoselective α-oxidation of the 10-membered lactone completed the center part to provide the key intermediate. Inspired by the degradation study, an unprecedented enol ether/maleic anhydride moiety was constructed with a one-pot chlorosulfide coupling and thiol ß-elimination sequence. Finally, macrolactonization to the 14-membered ring in the presence of the highly electrophilic maleic anhydride moiety was accomplished using modified Mukaiyama reagents to complete the synthesis of luminamicin.
Asunto(s)
Antibacterianos , Anhídridos Maleicos , Lactonas/química , Alquenos/química , EstereoisomerismoRESUMEN
We report a protoilludane-type sesquiterpene, mucoroidiol, and a geranylated bicyclogermacranol, firmibasiol, isolated from Dictyostelium cellular slime molds. The methanol extracts of the fruiting bodies of cellular slime molds were separated by chromatographic methods to give these compounds. Their structures have been established by several spectral means. Mucoroidiol and firmibasiol are the first examples of more modified and oxidized terpenoids isolated from cellular slime molds. Mucoroidiol showed moderate osteoclast-differentiation inhibitory activity despite demonstrating very weak cell-proliferation inhibitory activity. Therefore, cellular slime molds produce considerably diverse secondary metabolites, and they are promising sources of new natural product chemistry.
Asunto(s)
Dictyostelium/química , Terpenos/aislamiento & purificación , Animales , Antibacterianos/farmacología , Antineoplásicos/farmacología , Vías Biosintéticas/efectos de los fármacos , Dictyostelium/metabolismo , Escherichia coli/efectos de los fármacos , Células HeLa , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Ratones , Pruebas de Sensibilidad Microbiana , Osteogénesis/efectos de los fármacos , Células RAW 264.7 , Staphylococcus aureus/efectos de los fármacos , Terpenos/química , Terpenos/farmacologíaRESUMEN
The Huisgen cycloaddition of azides and alkynes, accelerated by target biomolecules, termed "in situ click chemistry," has been successfully exploited to discover highly potent enzyme inhibitors. We have previously reported a specific Serratia marcescens chitinase B (SmChiB)-templated syn-triazole inhibitor generated in situ from an azide-bearing inhibitor and an alkyne fragment. Several in situ click chemistry studies have been reported. Although some mechanistic evidence has been obtained, such as X-ray analysis of [protein]-["click ligand"] complexes, indicating that proteins act as both mold and template between unique pairs of azide and alkyne fragments, to date, observations have been based solely on "postclick" structural information. Here, we describe crystal structures of SmChiB complexed with an azide ligand and an O-allyl oxime fragment as a mimic of a click partner, revealing a mechanism for accelerating syn-triazole formation, which allows generation of its own distinct inhibitor. We have also performed density functional theory calculations based on the X-ray structure to explore the acceleration of the Huisgen cycloaddition by SmChiB. The density functional theory calculations reasonably support that SmChiB plays a role by the cage effect during the pretranslation and posttranslation states of selective syn-triazole click formation.
Asunto(s)
Azidas/química , Quitinasas/química , Química Clic/métodos , Modelos Moleculares , Oximas/química , Serratia marcescens/enzimología , Triazoles/química , Azidas/metabolismo , Quitinasas/antagonistas & inhibidores , Quitinasas/metabolismo , Cristalización , Estructura Molecular , Oximas/metabolismo , Teoría CuánticaRESUMEN
BACKGROUND: Streptococcus pneumoniae (pneumococcus) colonizes mucosal surfaces of the upper respiratory tract (URT), resulting in invasive disease. Macrolides are known for their immunomodulatory effects. We investigated the potency of macrolides to reduce pneumococcal colonization by activating host innate immunity. METHODS: The kinetics of colonization, cellular response, and inflammatory cytokine levels in the URT were assessed after nasal inoculation of pneumococci. EM900 (a novel 12-membered nonantibiotic macrolide with an immunomodulatory effect) was orally administered throughout the experiment. Survival was evaluated for 10 days. Macrolide-mediated CCL2 production from peritoneal macrophages was determined by enzyme-linked immuosorbent assay. The cell-signaling pathway was analyzed by means of Western blotting and gene silencing assays. RESULTS: Streptococcus pneumoniae was significantly reduced from EM900-treated mice 14 days after pneumococcal inoculation. Macrophage recruitment and Ccl2 messenger RNA expression were promoted. CCL2 production from peritoneal macrophages was significantly induced by macrolides and was dependent on NF-κB phosphorylation through the myeloid differentiation primary-response gene 88- or TIR domain-containing adapter-inducing interferon-ß-mediated pathway. Mortality of mice with invasive pneumococcal disease was improved by pretreatment with EM900. CONCLUSIONS: Macrolides may inhibit invasive pneumococcal infections by accelerating the clearance of pneumococcal nasopharyngeal colonization via promotion of macrophage-mediated innate immunity.
Asunto(s)
Antibacterianos/farmacología , Macrólidos/farmacología , Macrófagos/inmunología , Nasofaringe/microbiología , Infecciones Neumocócicas/inmunología , Streptococcus pneumoniae/inmunología , Animales , Antibacterianos/inmunología , Células Cultivadas , Quimiocina CCL2/metabolismo , Femenino , Inmunidad Innata , Interferón beta/inmunología , Macrólidos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/inmunología , Ratones , Ratones Endogámicos C57BL , FN-kappa B/inmunología , Fagocitosis/efectos de los fármacos , Infecciones Neumocócicas/prevención & control , Transducción de Señal/efectos de los fármacos , Organismos Libres de Patógenos Específicos , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
The total synthesis of the indole alkaloids, neoxaline, oxaline and meleagrinâ A, all containing a unique indoline spiroaminal framework, was accomplished through the stereoselective introduction of a reverse prenyl group to the congested benzylic carbon of furoindoline, a two-pot transformation of indoline (containing three nitrogen atoms at appropriate positions) to the featured indoline spiroaminal framework, and elimination of carbonate assisted by the adjacent imidazole moiety to construct the (E)-dehydrohistidine. The absolute stereochemistry of neoxaline was elucidated through our total synthesis. In addition, we evaluated the bioactivity, especially the anti-infectious properties, of neoxaline and oxaline, and of some synthetic intermediates.
RESUMEN
A first asymmetric total synthesis and determination of the absolute configuration of neoxaline has been accomplished through the highly stereoselective introduction of a reverse prenyl group to create a quaternary carbon stereocenter using (-)-3a-hydroxyfuroindoline as a building block, construction of the indoline spiroaminal via cautious stepwise oxidations with cyclizations from the indoline, assembly of (Z)-dehydrohistidine, and photoisomerization of unnatural (Z)-neoxaline to the natural (E)-neoxaline as the key steps.
Asunto(s)
Alcaloides/síntesis química , Alcaloides/química , Conformación Molecular , EstereoisomerismoRESUMEN
Borrelidin, a structurally unique 18-membered macrolide, was found to express antimalarial activity against drug-resistant Plasmodium falciparum malaria parasites, with IC50 value of 0.93 ng/mL. However, it also displays strong cytotoxicity against human diploid embryonic MRC-5 cells. To investigate the issue of the cytotoxicity of borrelidin, borrelidin-based analogues were synthesized and their anti-Plasmodium properties were evaluated. In this communication, we report that a novel borrelidin analogue, bearing the CH2SPh moiety via a triazole linkage, was found to retain a potent antimalarial activity, against drug-sensitive and drug-resistant parasite strains, but possess only weak cytotoxicity against human cells.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/síntesis química , Línea Celular , Alcoholes Grasos/síntesis química , Alcoholes Grasos/química , Alcoholes Grasos/farmacología , Humanos , Relación Estructura-ActividadRESUMEN
Human acidic mammalian chitinase (hAMCase) was recently shown to be involved in the development of asthma, suggesting a possible application for hAMCase inhibitors as novel therapeutic agents for asthma. We therefore initiated drug discovery research into hAMCase using a combination of in silico methodologies and a hAMCase assay system. We first selected 23 candidate hAMCase inhibitors from a database of four million compounds using a multistep screening system combining Tripos Topomer Search technology, a docking calculation and two-dimensional molecular similarity analysis. We then measured hAMCase inhibitory activity of the selected compounds and identified seven compounds with IC50 values ≤100 µM. A model describing the binding modes of these hit compounds to hAMCase was constructed, and we discuss the structure-activity relationships of the compounds we identified, suggested by the model and the actual inhibitory activities of the compounds.
Asunto(s)
Antiasmáticos/química , Quitinasas/antagonistas & inhibidores , Simulación del Acoplamiento Molecular , Péptidos Cíclicos/química , Sitios de Unión , Quitinasas/química , Simulación por Computador , Bases de Datos de Compuestos Químicos , Diseño de Fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Unión Proteica , Proteínas Recombinantes/química , Relación Estructura-ActividadRESUMEN
The three-dimensional (3D) structure of bottromycin A(2), a natural anti-methicillin-resistant Staphylococcus aureus (MRSA) and anti-vancomycin-resistant Enterococci (VRE) agent consisting of seven amino acids, has been investigated through NMR spectroscopy. On the basis of 57 experimental constraints, a total of 34 converged structures were obtained. The average pairwise atomic root mean square difference is 0.74±0.59 Å for all heavy atoms. The resulting structure indicates an interesting feature in that the three C-terminal residues of bottromycin A(2) fold back on the 12-membered cyclic skeleton made by the four N-terminal residues. Thus, MePro(2) and Thia-ß-Ala-OMe(7), modification of which significantly affects the antibacterial activities of bottromycin A(2), are located on one side of its 3D structure. These distinct structural features might be important for the binding of bottromycin A(2) with the bacterial ribosome.
Asunto(s)
Antibacterianos/química , Modelos Moleculares , Antibacterianos/farmacología , Enterococcus/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Soluciones/química , Resistencia a la VancomicinaRESUMEN
Genome mining and bioinformatics analyses allowed us to rationally find a candidate biosynthetic gene cluster for a new cyclic depsipeptide of Chaetomium mollipilium. A heterologous reconstitution of the identified biosynthetic pathway predictably afforded a new cyclic depsipeptide composed of l-leucine, l-tryptophan, and a polyketide moiety. Interestingly, the 10-membered macrocycle structure generated equilibrium to an unprecedented cyclol structure. This study demonstrates the advantage of a synthetic biology method in achieving rational access to new natural products.
Asunto(s)
Productos Biológicos , Chaetomium , Depsipéptidos , Policétidos , Productos Biológicos/química , Vías Biosintéticas , Chaetomium/genética , Depsipéptidos/química , Familia de Multigenes , Policétidos/químicaRESUMEN
Herein, we report the design and synthesis of the novel 12-membered non-antibiotic macrolide (8R,9S)-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM900), which was found to be a potent anti-inflammatory and/or immunomodulatory agent, capable of promoting monocyte to macrophage differentiation. This molecule shows improved acid stability, does not exhibit any anti-bacterial activity and has relatively low cytotoxicity against THP-1 cells. In addition, one of its analogues, (8R,9S)-4â³,13-O-diacetyl-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM911), was found to be twice as effective as EM900.
Asunto(s)
Antiinflamatorios/síntesis química , Diseño de Fármacos , Eritromicina/análogos & derivados , Eritromicina/química , Factores Inmunológicos/farmacología , Inmunomodulación/efectos de los fármacos , Macrólidos/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Eritromicina/síntesis química , Eritromicina/farmacología , Humanos , Factores Inmunológicos/síntesis química , Factores Inmunológicos/química , Macrólidos/síntesis química , Macrólidos/química , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura MolecularRESUMEN
The low-molecular-weight compound JRC-II-191 inhibits infection of HIV-1 by blocking the binding of the HIV-1 envelope glycoprotein gp120 to the CD4 receptor and is therefore an important lead in the development of a potent viral entry inhibitor. Reported here is the use of two orthogonal screening methods, gold docking and ROCS shape-based similarity searching, to identify amine-building blocks that, when conjugated to the core scaffold, yield novel analogs that maintain similar affinity for gp120. Use of this computational approach to expand SAR produced analogs of equal inhibitory activity but with diverse capacity to enhance viral infection. The novel analogs provide additional lead scaffolds for the development of HIV-1 entry inhibitors that employ protein-ligand interactions in the vestibule of gp120 Phe 43 cavity.
Asunto(s)
Fármacos Anti-VIH/farmacología , Antígenos CD4/metabolismo , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Diseño de Fármacos , Proteína gp120 de Envoltorio del VIH/metabolismo , Fusión de Membrana/efectos de los fármacos , Modelos Moleculares , Unión Proteica , Relación Estructura-ActividadRESUMEN
BACKGROUND/AIMS: Long-term macrolide therapy is an effective treatment for chronic sinusitis and diffuse panbronchiolitis. However, long-term use of macrolides may promote the growth of drug-resistant bacteria; therefore, development of macrolides with no antibacterial action is desirable. A new erythromycin (EM) derivative, (8R,9S)- 8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM900), does not possess antibacterial action. METHODS: To determine whether EM900 induced a clinically relevant anti-inflammatory response and repressed mucin gene expression in cells derived from human airway epithelia, we assessed the effects of EM900 on IL-1ß-induced inflammatory cytokines in A549 cells and MUC5AC gene expression in HM3-MUC5AC cells. We also investigated the effects of EM900 on IL-1ß-induced NF-κB activation. We performed reporter gene assays and quantitative PCR in A549 and HM3-MUC5AC cells. RESULTS: Both EM and EM900 suppressed IL-1ß-induced IL-8 expression in A549 cells. EM900 also suppressed IL-1ß-induced IL-1ß and TNF-α expression in A549 cells. EM900 inhibited IL-1ß-induced MUC5AC expression in HM3-MUC5AC cells. Both EM and EM900 suppressed IL-1ß-induced NF-κB activation in A549 cells. CONCLUSION: This study demonstrated that EM900 suppressed the induction of inflammatory cytokines and MUC5AC gene expression in cells derived from human airway epithelia, and our findings indicate that these effects may be mediated by the suppression of NF-κB activation.
Asunto(s)
Células Epiteliales/efectos de los fármacos , Eritromicina/análogos & derivados , Interleucina-8/genética , Macrólidos/farmacología , Mucina 5AC/genética , Factor de Necrosis Tumoral alfa/genética , Antiinflamatorios/farmacología , Línea Celular , Células Epiteliales/metabolismo , Eritromicina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-1beta/genética , Interleucina-1beta/farmacología , FN-kappa B/metabolismo , ARN Mensajero/metabolismoRESUMEN
Cancer immunotherapy involves the use of the immune system for cancer treatment. Recently, immune checkpoint-blocking antibodies have become integral for the treatment of some cancers. However, small molecules exhibit advantages over monoclonal antibody drugs, such as cell penetration, long half-life, and low manufacturing costs, and the possibility of oral administration. Thus, it is imperative to develop small-molecule immune checkpoint inhibitors. Previously, we have screened a library of synthetic indole-alkaloid-type compounds, which are produced by diversity-enhanced extracts of Japanese cornelian cherry, and reported that an unnatural pentacyclic compound inhibits CTLA-4 gene expression. In this study, immune checkpoint inhibitors with increased potency were developed by introducing substituents and conversion of functional groups based on the unnatural pentacyclic compound. The developed compounds suppressed not only CTLA-4 and PD-L1 gene expression but also protein expression on the cell surface. Their efficacy was not as potent as that of the existing small-molecule immune checkpoint inhibitors, but, to the best of our knowledge, the developed compounds are the first reported dual small-molecule inhibitors of CTLA-4 and PD-L1.
RESUMEN
Regio- and stereoselective hydrostannylation of alkyl ethynyl ethers generates alkenyl ethers, which are useful building blocks in organic synthesis. This efficient synthetic method, however, is limited. Here, we report not only an efficient method for a highly regio- and stereoselective Pd-catalyzed hydrostannylation of alkyl ethynyl ethers but also a scalable synthesis and construction of the core framework of luminamicin possessing all functional groups and stereocenters.
RESUMEN
The dipeptide N-acetyl-Arg{N(omega)-(N-methylcarbamoyl)}-N-methyl-Phe(2), which is a part of the natural-product cyclopentapeptide chitinase inhibitor argifin (1), inhibits chitinase B from Serratia marcescens (SmChiB) with a half-maximal inhibitory concentration (IC(50)) of 3.7 microM. Despite the relatively small size of 2, its inhibitory activity is comparable with that of 1 (IC(50)=6.4 microM). To elucidate the basis for this interesting phenomenon, we investigated the interaction between 2 and SmChiB using a combination of nuclear magnetic resonance spectroscopy and computational methods. The transferred nuclear Overhauser effect (TRNOE) experiment obtained structural information on the SmChiB-bound conformation of 2. The binding mode of 2 and SmChiB was modeled by the novel molecular-docking approach proposed in our laboratory, which can explicitly consider water-mediated hydrogen-bonding interactions in protein-ligand interfaces. The SmChiB-bound conformation of 2 in the resulting model satisfied all proton-proton distance constraints derived from the TRNOE experiment, indicating that our model structure of the 2-SmChiB complex is reasonable. A molecular dynamics (MD) simulation examined the stability of the resultant complex structure and suggested that 2 binds to SmChiB in a similar fashion to the binding mode observed for N(omega)-(N-methylcarbamoyl)-Arg(1) and N-methyl-Phe(2) of 1 in the crystal structure of the argifin-SmChiB complex. Finally, the binding free energies of 1 and 2 with SmChiB were estimated by the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method using the MD trajectory. The MM-PBSA calculation suggested that both 1 and 2 bind to SmChiB with similar affinities, which is consistent with their experimental IC(50) values. Energetic analysis revealed that the van der Waals interaction of 2 with SmChiB is much less than that of 1, but is completely compensated by the more favorable contribution of solute entropy and the total electrostatic component. The improved total electrostatic component was derived from more favorable electrostatic interactions. Therefore, we conclude that dipeptide 2 was also better optimized against SmChiB than 1 in an electrostatic point of view.