Multivariate epidemiologic analysis of type 2 diabetes mellitus risks in the Lebanese population

Background: The burden of diabetes in Lebanon requires well-targeted interventions for screening type 2 diabetes mellitus (T2DM) and prediabetes and prevention of risk factors. Newly recruited 998 Lebanese individuals, in addition to 7,292 already available, were studied to investigate the prevalence of diabetes, prediabetes and their associated risk factors. Methods: Participants had fasting blood sugar and glycohemoglobin tests in addition to a lipid profile. Clinical and demographic information were obtained from a detailed questionnaire. The relationship between T2DM, its risk factors, and its complications were tested. Comparisons of these risk factors among diabetics, healthy, and coronary artery disease (CAD) patients were performed. Results: The prevalence of T2DM significantly increased with increasing BMI (p < 0.0001). Exercise activity level negatively correlated with the disease (p = 0.002), whereas the prevalence of T2DM (p < 0.0001) and CAD family history (p = 0.006) positively correlated with the affection status. The mean levels of triglycerides and LDL-C were significantly higher in diabetics (1.87; 1.35) compared to individuals with prediabetes (1.63; 1.26) and unaffected controls (1.49; 1.19). People with T2DM showed a significant decrease in HDL-C levels. A strong correlation of overall hyperlipidemia with the diabetes affection status was shown (p < 0.0001). Other comorbid factors such as hypertension (p < 0.0001) and self-reported obesity (p < 0.0001) were highly associated with T2DM and prediabetes. Reproductive health of women showed a strong correlation between giving birth to a baby with a high weight and the occurrence of T2DM and prediabetes later in life (p < 0.0001). Retinopathy and peripheral neuropathy were significantly correlated with diabetes and prediabetes (p < 0.0001). Conclusions: The present study shows an alarming prevalence of diabetes and prediabetes in the studied subgroups representative of the Lebanese population. Electronic supplementary material The online version of this article (doi:10.1186/1758-5996-6-89) contains supplementary material, which is available to authorized users

Mechanisms of Resistance to Decitabine in the Myelodysplastic Syndrome

Purpose: The DNA methylation inhibitor 5-aza-29-deoxycytidine (DAC) is approved for the treatment of myelodysplastic syndromes (MDS), but resistance to DAC develops during treatment and mechanisms of resistance remain unknown. Therefore, we investigated mechanisms of primary and secondary resistance to DAC in MDS. Patients and Methods: We performed Quantitative Real-Time PCR to examine expression of genes related to DAC metabolism prior to therapy in 32 responders and non-responders with MDS as well as 14 patients who achieved a complete remission and subsequently relapsed while on therapy (secondary resistance). We then performed quantitative methylation analyses by bisulfite pyrosequencing of 10 genes as well as Methylated CpG Island Amplification Microarray (MCAM) analysis of global methylation in secondary resistance. Results: Most genes showed no differences by response, but the CDA/DCK ratio was 3 fold higher in non-responders than responders (P,.05), suggesting that this could be a mechanism of primary resistance. There were no significant differences at relapse in DAC metabolism genes, and no DCK mutations were detected. Global methylation measured by the LINE1 assay was lower at relapse than at diagnosis (P,.05). On average, the methylation of 10 genes was lower at relapse (16.1%) compared to diagnosis (18.1%) (P,.05).MCAM analysis showed decreased methylation of an average of 4.5 % (range 0.6%– 9.7%) of the genes at relapse. By contrast, new cytogenetic changes were found in 20 % of patients

Heterogeneity of the humoral immune response following Staphylococcus aureus bacteremia

Expanding knowledge on the humoral immune response in Staphylococcus aureus-infected patients is a mandatory step in the development of vaccines and immunotherapies. Here, we present novel insights into the antibody responses following S. aureus bacteremia. Fifteen bacteremic patients were followed extensively from diagnosis onwards (median 29 days, range 9-74). S. aureus strains (median 3, range 1-6) and serial serum samples (median 16, range 6-27) were collected. Strains were genotyped by pulsed-field gel electrophoresis (PFGE) and genes encoding 19 staphylococcal proteins were detected by polymerase chain reaction (PCR). The levels of IgG, IgA, and IgM directed to these proteins were determined using bead-based flow cytometry. All strains isolated from individual patients were PFGE-identical. The genes encoding clumping factor (Clf) A, ClfB, and iron-responsive surface-determinant (Isd) A were detected in all isolates. Antigen-specific IgG levels increased more frequently than IgA or IgM levels. In individual patients, different proteins induced an immune response and the dynamics clearly differed. Anti-ClfB, anti-IsdH, and anti-fibronectin-binding protein A IgG levels increased in 7 of 13 adult patients (p < 0.05). The anti-IsdA IgG level increased in 12 patients (initial to peak level: 1.13-10.72 fold; p < 0.01). Peak level was reached 7-37 days after diagnosis. In a bacteremic 5-day-old newborn, antistaphylococcal IgG levels declined from diagnosis onwards. In conclusion, each bacteremic patient develops a unique immune response directed to different staphylococcal proteins. Therefore, vaccines should be based on multiple components. IsdA is immunogenic and, therefore, produced in nearly all bacteremic patients.

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Analyse de systèmes complexes par dynamique moléculaire polarisable, vers une conception rationnelle de médicaments : des quadruplexes de Guanine au SARS-CoV-2

In silico design of new therapeutic molecules requires a detailed understanding of the structural dynamics of target proteins and nucleic acids. The objectives of this thesis are to apply molecular dynamics techniques coupled to polarizable force fields to complex biological systems of paramount importance within the framework of a rational design of anti-cancer and anti-viral drugs (inhibitors development). We chose to study Guanine quadruplexes (GQ) present at the level of c-kit 1 proto-oncogene and HIV-1 LTR-III as well as the main protease (Mpro) of SARS-CoV-2. Indeed, these target molecular complexes are of great biological and medical interest due to their involvement in serious diseases: cancer, AIDS and Covid-19. GQ structures are considered as emerging therapeutic targets as the transcriptional repression of genes by stabilizing these structures could be a new anti-cancer and anti-viral strategy. In addition, Mpro plays an essential role in the life cycle and replication of SARS-CoV-2. While this protease does not have a human homolog, it is an interesting anti-viral target. Thanks to the technological advances developed within our Laboratory, both at the computational level and at the level of accelerated sampling techniques in molecular dynamics based on PCA, we had the possibility to perform several µs of simulations in High-resolution molecular dynamics on large systems in explicit solvent and with a polarizable force field allowing to obtain a high precision in the prediction of the possible conformations of the studied systems. This allowed us to study the molecular dynamics of the main protease, Mpro of SARS-CoV-2 and of the guanine quadruplexes found in c-kit 1 promoter and HIV-1 LTR-III. The key structural markers related to the stability of the oxyanion holes of the Mpro reveal asymmetry between the protomers. The results highlight the plasticity of the active site and the presence of cryptic pockets. Analysis of solvation patterns at the active site and dimerization region demonstrates that confined AMOEBA polarizable water molecules are able to explore a wide range of dipole moments, leading to a consistent water molecule number with respect to experimental data. The data show the impact of protonation on the destructuring of the oxyanionic loop and the dimerization interface. Seven stable clusters were identified during MD of c-kit 1 GQ by tICA analysis, where the stability of the three stacked guanine tetrads and the long propeller loop were demonstrated. However the flexibility of the two single-nucleotide loops and one dinucleotide loop was analyzed by monitoring relevant inter-base distances, two key torsion angles, ? and ?, and ?-? stacking index. Two stable cryptic pockets were identified in the seven clusters, the grooves of which could serve as binding sites for pharmacological ligands. A preliminary CMD simulation on the GQ structure at the level of HIV-1 LTR-III was then performed. Two cryptic pockets have also been identified at its outcome, but their conformations differ significantly from those of c-kit 1 pockets, and only the former has been shown to be possibly viable for ligand design. The work done in this thesis suggests that the use of PFF could be critical in drug discovery to accurately model the complexity of molecular interactions. The results provide designers of therapeutic ligands with very high precision conformational space models ranging from Guanine quadruplexes to SARS-CoV-2 proteins.La conception de nouvelles molécules thérapeutiques in silico nécessite une compréhension fine de la dynamique structurale des protéines et des acide nucléiques cibles. Les objectifs de cette thèse sont d'appliquer les techniques de dynamique moléculaire couplées aux champs de forces polarisables à des systèmes biologiques complexes d'importance primordiale dans le cadre d'une conception rationnelle de médicaments anti-cancéreux et anti-viraux (mise au point d'inhibiteurs). Nous avons choisi d'étudier les quadruplexes de Guanine (GQ) au niveau du proto-oncogène c-kit 1 et de la région LTR-III du VIH-1 ainsi que la protéase principale (Mpro) du SARS-CoV-2. En effet, ces complexes moléculaires cibles présentent un fort intérêt biologique et médical du fait de leur implication dans des maladies graves : le cancer, le SIDA et le Covid-19. Les structures GQ sont considérées comme des cibles thérapeutiques émergentes vue que la répression transcriptionnelle des gènes par la stabilisation de ces structures pourrait être une nouvelle stratégie anti-cancéreuse et anti-virale. Par ailleurs, la Mpro, joue un rôle essentiel dans le cycle de vie et la réplication du SARS-CoV-2. Alors que cette protéase n'a pas d'homologue humain, il s'agit d'une cible anti-virale intéressante. Grâce aux avancés technologiques développées au sein de notre Laboratoire, tant au niveau informatique qu'au niveau des techniques d'échantillonnage accéléré en dynamique moléculaire basée sur la PCA, nous avions la possibilité d'effectuer plusieurs µs de simulations en dynamique moléculaire à haute-résolution sur des systèmes de grande taille en solvant explicite et avec un champ de forces polarisable permettant d'obtenir une haute précision dans la prédiction des conformations possibles des systèmes étudiés. Ceci nous a permis d'étudier finement la dynamique moléculaire de la protéase principale, Mpro du SARS-CoV-2 et des quadruplexes de guanine trouvés dans le promoteur de c-kit 1 et au niveau de la région LTR-III du VIH-1. Les marqueurs structurels clés liés à la stabilité des trous oxyanioniques de la Mpro révèlent une asymétrie entre les protomères. Les résultats mettent en évidence la plasticité du site actif et la présence des poches cryptiques. L'analyse des schémas de solvatation au niveau du site actif et de la région de dimérisation démontre que les molécules d'eau polarisables AMOEBA confinées sont capables d'explorer une large gamme de moments dipolaires, conduisant à un nombre de molécules d'eau cohérent avec les données expérimentales. Les données montrent l'impact de la protonation sur la déstructuration de la boucle oxyanionique et de l'interface de dimérisation. Sept clusters stables ont été identifiés au cours de MD du GQ de c-kit 1 par l'analyse tICA, où la stabilité des trois tétrades de guanine empilées et de la longue boucle d'hélice ont été mises en évidence. Cependant la flexibilité des deux boucles mononucléotidiques et d'une boucle dinucléotidique a été analysée en surveillant les distances inter-bases pertinentes, deux angles de torsion clés, ? et ?, et les indices d'empilement ?-?. Deux poches cryptiques stables ont été identifiées dans les sept clusters, dont les sillons pourraient servir de sites de liaison pour les ligands pharmacologiques. Une simulation CMD préliminaire sur la structure GQ au niveau de la LTR-III du VIH-1 a ensuite été effectuée. Deux poches cryptiques ont également été identifiées à son issue, mais leurs conformations diffèrent significativement de celles des poches c-kit 1, et seule la première s'est avérée possiblement viable pour la conception de ligands. Les travaux effectués dans cette thèse suggèrent que l'utilisation de PFF pourrait être critique dans la découverte de médicaments pour modéliser avec précision la complexité des interactions moléculaires. Les résultats offrent aux concepteurs de ligands thérapeutiques des modèles d'espaces conformationnels à très haute précision allant des quadruplexes [...

Analysis of complex systems by polarizable molecular dynamics, towards a rational drug design : from Guanine quadruplexes to SARS-CoV-2

La conception de nouvelles molécules thérapeutiques in silico nécessite une compréhension fine de la dynamique structurale des protéines et des acide nucléiques cibles. Les objectifs de cette thèse sont d'appliquer les techniques de dynamique moléculaire couplées aux champs de forces polarisables à des systèmes biologiques complexes d'importance primordiale dans le cadre d'une conception rationnelle de médicaments anti-cancéreux et anti-viraux (mise au point d'inhibiteurs). Nous avons choisi d'étudier les quadruplexes de Guanine (GQ) au niveau du proto-oncogène c-kit 1 et de la région LTR-III du VIH-1 ainsi que la protéase principale (Mpro) du SARS-CoV-2. En effet, ces complexes moléculaires cibles présentent un fort intérêt biologique et médical du fait de leur implication dans des maladies graves : le cancer, le SIDA et le Covid-19. Les structures GQ sont considérées comme des cibles thérapeutiques émergentes vue que la répression transcriptionnelle des gènes par la stabilisation de ces structures pourrait être une nouvelle stratégie anti-cancéreuse et anti-virale. Par ailleurs, la Mpro, joue un rôle essentiel dans le cycle de vie et la réplication du SARS-CoV-2. Alors que cette protéase n'a pas d'homologue humain, il s'agit d'une cible anti-virale intéressante. Grâce aux avancés technologiques développées au sein de notre Laboratoire, tant au niveau informatique qu'au niveau des techniques d'échantillonnage accéléré en dynamique moléculaire basée sur la PCA, nous avions la possibilité d'effectuer plusieurs µs de simulations en dynamique moléculaire à haute-résolution sur des systèmes de grande taille en solvant explicite et avec un champ de forces polarisable permettant d'obtenir une haute précision dans la prédiction des conformations possibles des systèmes étudiés. Ceci nous a permis d'étudier finement la dynamique moléculaire de la protéase principale, Mpro du SARS-CoV-2 et des quadruplexes de guanine trouvés dans le promoteur de c-kit 1 et au niveau de la région LTR-III du VIH-1. Les marqueurs structurels clés liés à la stabilité des trous oxyanioniques de la Mpro révèlent une asymétrie entre les protomères. Les résultats mettent en évidence la plasticité du site actif et la présence des poches cryptiques. L'analyse des schémas de solvatation au niveau du site actif et de la région de dimérisation démontre que les molécules d'eau polarisables AMOEBA confinées sont capables d'explorer une large gamme de moments dipolaires, conduisant à un nombre de molécules d'eau cohérent avec les données expérimentales. Les données montrent l'impact de la protonation sur la déstructuration de la boucle oxyanionique et de l'interface de dimérisation. Sept clusters stables ont été identifiés au cours de MD du GQ de c-kit 1 par l'analyse tICA, où la stabilité des trois tétrades de guanine empilées et de la longue boucle d'hélice ont été mises en évidence. Cependant la flexibilité des deux boucles mononucléotidiques et d'une boucle dinucléotidique a été analysée en surveillant les distances inter-bases pertinentes, deux angles de torsion clés, ? et ?, et les indices d'empilement ?-?. Deux poches cryptiques stables ont été identifiées dans les sept clusters, dont les sillons pourraient servir de sites de liaison pour les ligands pharmacologiques. Une simulation CMD préliminaire sur la structure GQ au niveau de la LTR-III du VIH-1 a ensuite été effectuée. Deux poches cryptiques ont également été identifiées à son issue, mais leurs conformations diffèrent significativement de celles des poches c-kit 1, et seule la première s'est avérée possiblement viable pour la conception de ligands. Les travaux effectués dans cette thèse suggèrent que l'utilisation de PFF pourrait être critique dans la découverte de médicaments pour modéliser avec précision la complexité des interactions moléculaires. Les résultats offrent aux concepteurs de ligands thérapeutiques des modèles d'espaces conformationnels à très haute précision allant des quadruplexes [...]In silico design of new therapeutic molecules requires a detailed understanding of the structural dynamics of target proteins and nucleic acids. The objectives of this thesis are to apply molecular dynamics techniques coupled to polarizable force fields to complex biological systems of paramount importance within the framework of a rational design of anti-cancer and anti-viral drugs (inhibitors development). We chose to study Guanine quadruplexes (GQ) present at the level of c-kit 1 proto-oncogene and HIV-1 LTR-III as well as the main protease (Mpro) of SARS-CoV-2. Indeed, these target molecular complexes are of great biological and medical interest due to their involvement in serious diseases: cancer, AIDS and Covid-19. GQ structures are considered as emerging therapeutic targets as the transcriptional repression of genes by stabilizing these structures could be a new anti-cancer and anti-viral strategy. In addition, Mpro plays an essential role in the life cycle and replication of SARS-CoV-2. While this protease does not have a human homolog, it is an interesting anti-viral target. Thanks to the technological advances developed within our Laboratory, both at the computational level and at the level of accelerated sampling techniques in molecular dynamics based on PCA, we had the possibility to perform several µs of simulations in High-resolution molecular dynamics on large systems in explicit solvent and with a polarizable force field allowing to obtain a high precision in the prediction of the possible conformations of the studied systems. This allowed us to study the molecular dynamics of the main protease, Mpro of SARS-CoV-2 and of the guanine quadruplexes found in c-kit 1 promoter and HIV-1 LTR-III. The key structural markers related to the stability of the oxyanion holes of the Mpro reveal asymmetry between the protomers. The results highlight the plasticity of the active site and the presence of cryptic pockets. Analysis of solvation patterns at the active site and dimerization region demonstrates that confined AMOEBA polarizable water molecules are able to explore a wide range of dipole moments, leading to a consistent water molecule number with respect to experimental data. The data show the impact of protonation on the destructuring of the oxyanionic loop and the dimerization interface. Seven stable clusters were identified during MD of c-kit 1 GQ by tICA analysis, where the stability of the three stacked guanine tetrads and the long propeller loop were demonstrated. However the flexibility of the two single-nucleotide loops and one dinucleotide loop was analyzed by monitoring relevant inter-base distances, two key torsion angles, ? and ?, and ?-? stacking index. Two stable cryptic pockets were identified in the seven clusters, the grooves of which could serve as binding sites for pharmacological ligands. A preliminary CMD simulation on the GQ structure at the level of HIV-1 LTR-III was then performed. Two cryptic pockets have also been identified at its outcome, but their conformations differ significantly from those of c-kit 1 pockets, and only the former has been shown to be possibly viable for ligand design. The work done in this thesis suggests that the use of PFF could be critical in drug discovery to accurately model the complexity of molecular interactions. The results provide designers of therapeutic ligands with very high precision conformational space models ranging from Guanine quadruplexes to SARS-CoV-2 proteins

An Efficient 3-D FDTD-PE Hybrid Model for Radio Wave Propagation With Near-Source Obstacles

International audienc