Sesamin and sesamol attenuate H2O2-induced oxidative stress on human neuronal cells via the SIRT1-SIRT3-FOXO3a signaling pathway.

Background: An imbalance of free radicals and antioxidant defense systems in physiological processes can result in protein/DNA damage, inflammation, and cellular apoptosis leading to neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Sesamin and sesamol, compounds derived from sesame seeds and oil, have been reported to exert various pharmacological effects, especially antioxidant activity. However, their molecular mechanisms against the oxidative stress induced by exogenous hydrogen peroxide (H2O2) remain to be elucidated. Aim: In this study, neuroprotective effects of sesamin and sesamol on H2O2-induced human neuroblastoma (SH-SY5Y) cell death and possible signaling pathways in the cells were explored. Methods: MTT assay and flow cytometry were conducted to determine cell viability and apoptotic profiles of neuronal cells treated with sesamin and sesamol. Carboxy-DCFDA assay was used to measure reactive oxygen species (ROS). Moreover, Western blot analysis was performed to investigate protein profiles associated with neuroprotection. Results: Pretreatment of the cells with 1 µM of sesamin and sesamol remarkably reduced the SH-SY5Y cell death induced by 400 µM H2O2 as well as the intracellular ROS production. Moreover, the molecular mechanisms underlying neuroprotection of the compounds were associated with activating SIRT1-SIRT3-FOXO3a expression, inhibiting BAX (proapoptotic protein), and upregulating BCL-2 (anti-apoptotic protein). Conclusion: The findings suggest that sesamin and sesamol are compounds that potentially protect neuronal cells against oxidative stress similar to that of the resveratrol, the reference compound. These antioxidants are thus of interest for further investigation in in vivo models of neuroprotection.

Synthesis and neuroprotective effects of novel chalcone-triazole hybrids.

The development of novel neuroprotective agents is urgently needed for the treatment of neurodegenerative diseases, affecting aging individuals worldwide. In this study, a new set of chalcone-triazole hybrids (6a-g) was synthesized and evaluated for their biological properties including cytotoxicity, antioxidant, anti-apoptosis, and neuroprotection using SH-SY5Y cells. The results showed that 6a and 6e provided neuroprotection in oxidative stress-induced neuronal cell damage. Both compounds significantly improved the morphology of neurons and obviously increased cell survival rate of neuronal cells induced by oxidative stress. Additionally, 6a and 6e counteracted H2O2­induced mitochondrial dysfunction, which was supported by maintaining mitochondrial membrane potential, attenuating BAX protein, and increasing BCL­2 protein within the mitochondria as well as upregulating SOD2 mitochondrial antioxidant enzyme. Interestingly, these compounds promoted neuroprotection via SIRT-FOXO3a signaling pathway similar to resveratrol. The data indicated that the chalcone-triazole derivatives (6a and 6e) could be considered to be promising compounds toward the discovery of disease-modifying candidates for a neurodegenerative therapy.

Discovery of novel halogenated 8-hydroxyquinoline-based anti-MRSA agents: In vitro and QSAR studies.

Methicillin-resistant Staphylococcus aureus (MRSA) infection has been considered to be one of global health problems due to limited classes of effective antimicrobial drugs. Herein, 8-hydroxyquinoline (8HQ) and its derivatives (1-7) were investigated for their anti-MRSA and antioxidant activities. Cloxyquin (2), a halogenated 8HQ, exerted the highest antimicrobial activity (MIC50 ≤ 5.57 µM) with high safety index, whereas an amino-derivative 7 showed the strongest antioxidant activity. Additionally, quantitative structure-activity relationship (QSAR) study demonstrated that mass, polarizability, topological charge, and van der Waals volume are essential properties governing the anti-MRSA activity. Taken together, cloxyquin was highlighted as a promising compound for further development as a novel anti-MRSA agent. QSAR findings would also benefit for further rational design of novel 8HQ-based compounds to combat the MRSA resistance.

Repurposing of Nitroxoline Drug for the Prevention of Neurodegeneration.

Oxidative stress has been documented as one of the significant causes of neurodegenerative diseases. Therefore, antioxidant therapy for the prevention of neurodegenerative diseases seems to be an interesting strategy in drug discovery. The quinoline-based compound, namely 5-nitro-8-quinolinol (NQ), has shown excellent antimicrobial, anticancer, and anti-inflammatory activities. However, its neuroprotective effects and precise molecular mechanisms in human neuronal cells have not been elucidated. In this work, the effects of NQ on cell viability and morphology were evaluated by the MTT assay and microscopic observation. Moreover, the underlying mechanisms of this compound, inducing the survival rate of neuronal cells under oxidative stress, were investigated by reactive oxygen species (ROS) assay, flow cytometry, Western blotting, and immunofluorescence techniques. In addition, the molecular interaction of sirtuin1 (SIRT1) with NQ was constructed using the AutoDock 4.2 program. Interestingly, NQ protected SH-SY5Y cells against H2O2-induced neurotoxicity through scavenging ROS, upregulating the levels of SIRT1 and FOXO3a, increasing the levels of antioxidant enzymes (catalase and superoxide dismutase), promoting antiapoptotic BCL-2 protein expression, and reducing apoptosis. Besides, molecular docking also revealed that NQ interacted satisfactorily with the active site of SIRT1 similar to the resveratrol, which is the SIRT1 activator and strong antioxidant. These findings suggest that NQ prevents oxidative-stress-induced neurodegeneration because of its antioxidant capacity as well as antiapoptotic property through SIRT1-FOXO3a signaling pathway. Thus, NQ might be a drug that could be repurposed for prevention of neurodegeneration.

Synthesis, molecular docking, and QSAR study of bis-sulfonamide derivatives as potential aromatase inhibitors.

A library of bis-sulfonamides (9-26) were synthesized and tested for their aromatase inhibitory activities. Interestingly, all bis-sulfonamide derivatives inhibited the aromatase with IC50 range of 0.05-11.6 µM except for compound 23. The analogs 15 and 16 bearing hydrophobic chloro and bromo groups exhibited the potent aromatase inhibitory activity in sub-micromolar IC50 values (i.e., 50 and 60 nM, respectively) with high safety index. Molecular docking revealed that the chloro and bromo benzenesulfonamides (15 and 16) may play role in the hydrophobic interaction with Leu477 of the aromatase to mimic steroidal backbone of the natural substrate, androstenedione. QSAR study also revealed that the most potent activity of compounds was governed by van der Waals volume (GATS6v) and mass (Mor03m) descriptors. Finally, the two compounds (15 and 16) were highlighted as promising compounds to be further developed as novel aromatase inhibitors.

Novel triazole-tetrahydroisoquinoline hybrids as human aromatase inhibitors.

Novel thirteen triazole-tetrahydroisoquinoline derivatives (2a-m) were synthesized and evaluated for their aromatase inhibitory activities. Seven triazoles showed significant aromatase inhibitory activity (IC50 = 0.07-1.9 µM). Interestingly, the analog bearing naphthalenyloxymethyl substituent at position 4 of the triazole ring (2i) displayed the most potent aromatase inhibitory activity (IC50 = 70 nM) without significant cytotoxicity to a normal cell. Molecular docking also suggested that the direct H-bonding interaction with residue Thr310 may be responsible for a striking inhibitory effect of the most potent compound 2i.

Meta-iAVP: A Sequence-Based Meta-Predictor for Improving the Prediction of Antiviral Peptides Using Effective Feature Representation.

In spite of the large-scale production and widespread distribution of vaccines and antiviral drugs, viruses remain a prominent human disease. Recently, the discovery of antiviral peptides (AVPs) has become an influential antiviral agent due to their extraordinary advantages. With the avalanche of newly-found peptide sequences in the post-genomic era, there is a great demand to develop a sequence-based predictor for timely identifying AVPs as this information is very useful for both basic research and drug development. In this study, we propose a novel sequence-based meta-predictor with an effective feature representation, called Meta-iAVP, for the accurate prediction of AVPs from given peptide sequences. Herein, the effective feature representation was extracted from a set of prediction scores derived from various machine learning algorithms and types of features. To the best of our knowledge, the model proposed herein represents the first meta-based approach for the prediction of AVPs. An overall accuracy and Matthews correlation coefficient of 95.20% and 0.90, respectively, was achieved from the independent test set on an objective benchmark dataset. Comparative analysis suggested that Meta-iAVP was superior to that of existing methods and therefore represents a useful tool for AVP prediction. Finally, in an effort to facilitate high-throughput prediction of AVPs, the model was deployed as the Meta-iAVP web server and is made freely available online at http://codes.bio/meta-iavp/ where users can submit query peptide sequences for determining the likelihood of whether or not these peptides are AVPs.

Insight into the Molecular Interaction of Cloxyquin (5-chloro-8-hydroxyquinoline) with Bovine Serum Albumin: Biophysical Analysis and Computational Simulation.

Cloxyquin is a potential therapeutic compound possessing various bioactivities, especially antibacterial, antifungal, cardioprotective, and pain relief activities. Herein, the interaction mechanism between cloxyquin and bovine serum albumin (BSA) has been elucidated in order to fulfill its pharmacokinetic and pharmacodynamic gaps essential for further development as a therapeutic drug. Multi-spectroscopic and biophysical model analysis suggested that cloxyquin interacts with BSA via a static process by ground-state complex formation. Its binding behavior emerged as a biphasic fashion with a moderate binding constant at the level of 104 M-1. Thermodynamic analysis and molecular docking simulation concurrently revealed that hydrophobic interaction is a major driving force for BSA-cloxyquin complexation. Binding of cloxyquin tends to slightly enlarge the monomeric size of BSA without a significant increase of aggregate fraction. Cloxyquin preferentially binds into the fatty acid binding site 5 (FA5) of the BSA via hydrophobic interaction amongst its quinoline scaffold and Phe550, Leu531, and Leu574 residues of BSA. The quinoline ring and hydroxyl moiety of cloxyquin also form the π-π interaction and the hydrogen bond with Phe506. Our data indicate a potential function of serum albumin as a carrier of cloxyquin in blood circulation.

TargetAntiAngio: A Sequence-Based Tool for the Prediction and Analysis of Anti-Angiogenic Peptides.

Cancer remains one of the major causes of death worldwide. Angiogenesis is crucial for the pathogenesis of various human diseases, especially solid tumors. The discovery of anti-angiogenic peptides is a promising therapeutic route for cancer treatment. Thus, reliably identifying anti-angiogenic peptides is extremely important for understanding their biophysical and biochemical properties that serve as the basis for the discovery of new anti-cancer drugs. This study aims to develop an efficient and interpretable computational model called TargetAntiAngio for predicting and characterizing anti-angiogenic peptides. TargetAntiAngio was developed using the random forest classifier in conjunction with various classes of peptide features. It was observed via an independent validation test that TargetAntiAngio can identify anti-angiogenic peptides with an average accuracy of 77.50% on an objective benchmark dataset. Comparisons demonstrated that TargetAntiAngio is superior to other existing methods. In addition, results revealed the following important characteristics of anti-angiogenic peptides: (i) disulfide bond forming Cys residues play an important role for inhibiting blood vessel proliferation; (ii) Cys located at the C-terminal domain can decrease endothelial formatting activity and suppress tumor growth; and (iii) Cyclic disulfide-rich peptides contribute to the inhibition of angiogenesis and cell migration, selectivity and stability. Finally, for the convenience of experimental scientists, the TargetAntiAngio web server was established and made freely available online.

Production and Characterization of Recombinant Wild Type Uricase from Indonesian Coelacanth (L. menadoensis) and Improvement of Its Thermostability by In Silico Rational Design and Disulphide Bridges Engineering.

The ideal therapeutic uricase (UOX) is expected to have the following properties; high expression level, high activity, high thermostability, high solubility and low immunogenicity. The latter property is believed to depend largely on sequence identity to the deduced human UOX (dH-UOX). Herein, we explored L. menadoensis uricase (LM-UOX) and found that it has 65% sequence identity to dH-UOX, 68% to the therapeutic chimeric porcine-baboon UOX (PBC) and 70% to the resurrected ancient mammal UOX. To study its biochemical properties, recombinant LM-UOX was produced in E. coli and purified to more than 95% homogeneity. The enzyme had specific activity up to 10.45 unit/mg, which was about 2-fold higher than that of the PBC. One-litre culture yielded purified protein up to 132 mg. Based on homology modelling, we successfully engineered I27C/N289C mutant, which was proven to contain inter-subunit disulphide bridges. The mutant had similar specific activity and production yield to that of wild type (WT) but its thermostability was dramatically improved. Up on storage at -20 °C and 4 °C, the mutant retained ~100% activity for at least 60 days. By keeping at 37 °C, the mutant retained ~100% activity for 15 days, which was 120-fold longer than that of the wild type. Thus, the I27C/N289C mutant has potential to be developed for treatment of hyperuricemia.

ACPred: A Computational Tool for the Prediction and Analysis of Anticancer Peptides.

Anticancer peptides (ACPs) have emerged as a new class of therapeutic agent for cancer treatment due to their lower toxicity as well as greater efficacy, selectivity and specificity when compared to conventional small molecule drugs. However, the experimental identification of ACPs still remains a time-consuming and expensive endeavor. Therefore, it is desirable to develop and improve upon existing computational models for predicting and characterizing ACPs. In this study, we present a bioinformatics tool called the ACPred, which is an interpretable tool for the prediction and characterization of the anticancer activities of peptides. ACPred was developed by utilizing powerful machine learning models (support vector machine and random forest) and various classes of peptide features. It was observed by a jackknife cross-validation test that ACPred can achieve an overall accuracy of 95.61% in identifying ACPs. In addition, analysis revealed the following distinguishing characteristics that ACPs possess: (i) hydrophobic residue enhances the cationic properties of α-helical ACPs resulting in better cell penetration; (ii) the amphipathic nature of the α-helical structure plays a crucial role in its mechanism of cytotoxicity; and (iii) the formation of disulfide bridges on ß-sheets is vital for structural maintenance which correlates with its ability to kill cancer cells. Finally, for the convenience of experimental scientists, the ACPred web server was established and made freely available online.

Neuroprotective Effects of Phenolic and Carboxylic Acids on Oxidative Stress-Induced Toxicity in Human Neuroblastoma SH-SY5Y Cells.

An increase in oxidative stress is a key factor responsible for neurotoxicity induction and cell death leading to neurodegenerative diseases including Parkinson's and Alzheimer's diseases. Plant phenolics exert diverse bioactivities i.e., antioxidant, anti-inflammatory, and neuroprotective effects. Herein, phenolic compounds, namely protocatechuic aldehyde (PCA) constituents of Hydnophytum formicarum Jack. including vanillic acid (VA) and trans-ferulic acid (FA) found in Spilanthes acmella Murr., were explored for anti-neurodegenerative properties using an in vitro model of oxidative stress-induced neuroblastoma SH-SY5Y cells. Exposure of the neuronal cells with H2O2 resulted in the decrease of cell viability, but increasing in the level of reactive oxygen species (ROS) together with morphological changes and inducing cellular apoptosis. SH-SY5Y cells pretreated with 5 µM of PCA, VA, and FA were able to attenuate cell death caused by H2O2-induced toxicity, as well as decreased ROS level and apoptotic cells after 24 h of treatment. Pretreated SH-SY5Y cells with phenolic compounds also helped to upregulate H2O2-induced depletion of the expressions of sirtuin-1 (SIRT1) and forkhead box O (FoxO) 3a as well as induce the levels of antioxidant (superoxide dismutase (SOD) 2 and catalase) and antiapoptotic B-cell lymphoma 2 (Bcl-2) proteins. The findings suggest that these phenolics might be promising compounds against neurodegeneration.

Synthesis and molecular docking of N,N'-disubstituted thiourea derivatives as novel aromatase inhibitors.

A three series of thioureas, monothiourea type I (4a-g), 1,4-bisthiourea type II (5a-h) and 1,3-bisthiourea type III (6a-h) were synthesized. Their aromatase inhibitory activities have been evaluated. Interestingly, eight thiourea derivatives (4e, 5f-h, 6d, 6f-h) exhibited the aromatase inhibitory activities with IC50 range of 0.6-10.2 µM. The meta-bisthiourea bearing 4-NO2 group (6f) and 3,5-diCF3 groups (6h) were shown to be the most potent compounds with sub-micromolar IC50 values of 0.8 and 0.6 µM, respectively. Molecular docking also revealed that one of the thiourea moieties of these two compounds could mimic steroidal backbone of the natural androstenedione (ASD) via hydrophobic interactions with enzyme residues (Val370, Leu477, Thr310, and Phe221 for 6f, Val370, Leu477, Ser478, and Ile133 for 6h). This is the first time that the bisthioureas have been reported for their potential to be developed as aromatase inhibitors, in which the 4-NO2 and 3,5-diCF3 analogs have been highlighted as promising candidates.

Multiplex PCR scheme for variant plasmid mediated class C ß-lactamase typing.

BACKGROUND: An increasing of prevalence and diversification of plasmid-mediated AmpC (pAmpC) has been emerged worldwide. The incidence of pAmpC resulted in increasing ß-lactamase production and conferred resistance to almost all ß-lactam antibiotics excluding carbapenems. The lack of standard method for pAmpC identification and classification exert a challenge in epidemiological surveillance and infection control practices. METHODS: A robust, single tube multiplex PCR has been developed to classify six different pAmpC groups including CIT (CMY-2 like, LAT and CFE), ECB (ACT, MIR), MOX & CMY-1 like, DHA, ACC, and FOX. The developed method was optimized and validated by testing of sensitivity and specificity. RESULTS: Developed method can detect crude extracted DNA template at nano-scale (2.5 ηg) and has high discriminatory power as compared to phenotypic and commercial genotypic method. CONCLUSION: The developed method can be utilized for tracking the changes of clinically important resistance patterns and further investigation of occurrence and distribution of plasmid-mediated AmpC types.

Structural and biochemical characterization of two heme binding sites on α1-microglobulin using site directed mutagenesis and molecular simulation.

BACKGROUND: α1-Microglobulin (A1M) is a reductase and radical scavenger involved in physiological protection against oxidative damage. These functions were previously shown to be dependent upon cysteinyl-, C34, and lysyl side-chains, K(92, 118,130). A1M binds heme and the crystal structure suggests that C34 and H123 participate in a heme binding site. We have investigated the involvement of these five residues in the interactions with heme. METHODS: Four A1M-variants were expressed: with cysteine to serine substitution in position 34, lysine to threonine substitutions in positions (92, 118, 130), histidine to serine substitution in position 123 and a wt without mutations. Heme binding was investigated by tryptophan fluorescence quenching, UV-Vis spectrophotometry, circular dichroism, SPR, electrophoretic migration shift, gel filtration, catalase-like activity and molecular simulation. RESULTS: All A1M-variants bound to heme. Mutations in C34, H123 or K(92, 118, 130) resulted in significant absorbance changes, CD spectral changes, and catalase-like activity, suggesting involvement of these side-groups in coordination of the heme-iron. Molecular simulation support a model with two heme-binding sites in A1M involving the mutated residues. Binding of the first heme induces allosteric stabilization of the structure predisposing for a better fit of the second heme. CONCLUSIONS: The results suggest that one heme-binding site is located in the lipocalin pocket and a second binding site between loops 1 and 4. Reactions with the hemes involve the side-groups of C34, K(92, 118, 130) and H123. GENERAL SIGNIFICANCE: The model provides a structural basis for the functional activities of A1M: heme binding activity of A1M.

Prevalence of Thalassemia Traits and Iron Deficiency Anemia in Sindh, Pakistan.

Among microcytic hypochromic anemias, the most common disorders are iron deficiency anemia and co-pathological conditions such as α- or ß-thalassemia (α- or ß-thal) traits. The aim of the present study was to determine the frequency and prevalence of iron deficiency anemia and α- or ß-thal traits based on clinical laboratory data across different ethnic groups in five districts of Sindh Province, Pakistan. The present retrospective study analyzed 3 years (2012-2015) of encoded and unlinked clinical laboratory data, and identified 3030 microcytic hypochromic anemia cases. The data contained complete blood counts (CBCs) with smear morphology examinations, serum ferritin levels, and hemoglobin (Hb) electrophoreses. After reviewing the data, 994 confirmed subjects (iron deficiency anemia and α- and ß-thal traits) were then selected for the present study. The prevalence of α- and ß-thal traits was highest in Badin district (35.27%), while the prevalence of iron deficiency anemia was highest in Larkana district (30.73%). According to the ethnic-wise distribution, higher numbers of α- and ß-thal trait cases were seen in the Sindhi ethnic group [375 (64.21%) and 283 (69.02%), respectively] than in the other ethnic groups. In addition, a higher distribution of ß-thal trait cases was observed in the Sindhi ethnic group [n = 327 (56%)] in α- and ß-thal cases overall. Findings from the present study strongly suggested that screening is important not only for ß-thal trait but also other traits as well. However, careful monitoring of CBC parameters, including red blood cell (RBC) indices and morphology, along with clinical findings are essential to diagnose carrier cases, especially in high prevalence areas.

Food safety in Thailand. 3: Pesticide residues detected in mangosteen (Garcinia mangostana L.), queen of fruits.

BACKGROUND: For developing countries like Thailand, regulation of pesticide usage exists, but it is not fully enforced. Therefore, pesticide residues in vegetables and fruits have not been well monitored. This study aimed to determine the pesticide residues in mangosteen fruits sold in Thailand. The mangosteen samples (n = 111) were purchased and the contents of 28 pesticides were analysed by GC-MS/MS method. RESULTS: Of the pesticides tested, eight were found in 100% of the mangosteen samples. However, in 97% of these samples, either chlorothalonil, chlorpyrifos, diazinon, dimethoate, metalaxyl or profenofos was detected exceeding their maximum residue limits (MRLs), representing a 97% rate of pesticide detection above the MRL. This rate is much higher than those found in other fruits sold in developed countries. However, this conclusion excludes the fresh Thai mangosteens grown for export, as these are generally cultivated and harvested to GAP standards. Since the edible part of the mangosteen is the pulp, washing the fruits with running water can reduce the risk of pesticide residues contaminating the pulp which would be eaten by the consumer. CONCLUSION: The findings strongly suggest that routine monitoring of pesticide residues in fruits and vegetables is required to reduce the health risks associated with consuming contaminated food. © 2016 Society of Chemical Industry.

Osteoporosis: the current status of mesenchymal stem cell-based therapy.

Osteoporosis, or bone loss, is a progressive, systemic skeletal disease that affects millions of people worldwide. Osteoporosis is generally age related, and it is underdiagnosed because it remains asymptomatic for several years until the development of fractures that confine daily life activities, particularly in elderly people. Most patients with osteoporotic fractures become bedridden and are in a life-threatening state. The consequences of fracture can be devastating, leading to substantial morbidity and mortality of the patients. The normal physiologic process of bone remodeling involves a balance between bone resorption and bone formation during early adulthood. In osteoporosis, this process becomes imbalanced, resulting in gradual losses of bone mass and density due to enhanced bone resorption and/or inadequate bone formation. Several growth factors underlying age-related osteoporosis and their signaling pathways have been identified, such as osteoprotegerin (OPG)/receptor activator of nuclear factor B (RANK)/RANK ligand (RANKL), bone morphogenetic protein (BMP), wingless-type MMTV integration site family (Wnt) proteins and signaling through parathyroid hormone receptors. In addition, the pathogenesis of osteoporosis has been connected to genetics. The current treatment of osteoporosis predominantly consists of antiresorptive and anabolic agents; however, the serious adverse effects of using these drugs are of concern. Cell-based replacement therapy via the use of mesenchymal stem cells (MSCs) may become one of the strategies for osteoporosis treatment in the future.

Roles of d-Amino Acids on the Bioactivity of Host Defense Peptides.

Host defense peptides (HDPs) are positively-charged and amphipathic components of the innate immune system that have demonstrated great potential to become the next generation of broad spectrum therapeutic agents effective against a vast array of pathogens and tumor. As such, many approaches have been taken to improve the therapeutic efficacy of HDPs. Amongst these methods, the incorporation of d-amino acids (d-AA) is an approach that has demonstrated consistent success in improving HDPs. Although, virtually all HDP review articles briefly mentioned about the role of d-AA, however it is rather surprising that no systematic review specifically dedicated to this topic exists. Given the impact that d-AA incorporation has on HDPs, this review aims to fill that void with a systematic discussion of the impact of d-AA on HDPs.

Proteochemometric model for predicting the inhibition of penicillin-binding proteins.

Neisseria gonorrhoeae infection threatens to become an untreatable sexually transmitted disease in the near future owing to the increasing emergence of N. gonorrhoeae strains with reduced susceptibility and resistance to the extended-spectrum cephalosporins (ESCs), i.e. ceftriaxone and cefixime, which are the last remaining option for first-line treatment of gonorrhea. Alteration of the penA gene, encoding penicillin-binding protein 2 (PBP2), is the main mechanism conferring penicillin resistance including reduced susceptibility and resistance to ESCs. To predict and investigate putative amino acid mutations causing ß-lactam resistance particularly for ESCs, we applied proteochemometric modeling to generalize N. gonorrhoeae susceptibility data for predicting the interaction of PBP2 with therapeutic ß-lactam antibiotics. This was afforded by correlating publicly available data on antimicrobial susceptibility of wild-type and mutant N. gonorrhoeae strains for penicillin-G, cefixime and ceftriaxone with 50 PBP2 protein sequence data using partial least-squares projections to latent structures. The generated model revealed excellent predictability (R2=0.91, Q2=0.77, QExt2=0.78). Moreover, our model identified amino acid mutations in PBP2 with the highest impact on antimicrobial susceptibility and provided information on physicochemical properties of amino acid mutations affecting antimicrobial susceptibility. Our model thus provided insight into the physicochemical basis for resistance development in PBP2 suggesting its use for predicting and monitoring novel PBP2 mutations that may emerge in the future.