Multi-target potential of Indian phytochemicals against SARS-CoV-2: A docking, molecular dynamics and MM-GBSA approach extended to Omicron B.1.1.529.

BACKGROUND: SARS-CoV-2, an emerged strain of corona virus family became almost serious health concern worldwide. Despite vaccines availability, reports suggest the occurrence of SARS-CoV-2 infection even in a vaccinated population. With frequent evolution and expected multiple COVID-19 waves, improved preventive, diagnostic, and treatment measures are required. In recent times, phytochemicals have gained attention due to their therapeutic characteristics and are suggested as alternative and complementary treatments for infectious diseases. This present study aimed to identify potential inhibitors against reported protein targets of SARS-CoV-2. METHODOLOGY: We computationally investigated potential SARS-CoV-2 protein targets from the literature and collected druggable phytochemicals from Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT) database. Further, we implemented a systematic workflow of molecular docking, dynamic simulations and generalized born surface area free-energy calculations (MM-GBSA). RESULTS: Extensive literature search and assessment of 1508 articles identifies 13 potential SARS-CoV-2 protein targets. We screened 501 druggable phytochemicals with proven biological activities. Analysis of 6513(501 *13) docked phytochemicals complex, 26 were efficient against SARS-CoV-2. Amongst, 4,8-dihydroxysesamin and arboreal from Gmelina arborea were ranked potential against most of the targets with binding energy ranging between - 10.7 to - 8.2 kcal/mol. Additionally, comparative docking with known drugs such as arbidol (-6.6 to -5.1 kcal/mol), favipiravir (-5.5 to -4.5 kcal/mol), hydroxychloroquine (-6.5 to -5.1 kcal/mol), and remedesivir (-8.0 to -5.3 kcal/mol) revealed equal/less affinity than 4,8-dihydroxysesamin and arboreal. Interestingly, the nucleocapsid target was found commonly inhibited by 4,8-dihydroxysesamin and arboreal. Molecular dynamic simulation and Molecular mechanics generalized born surface area (MM-GBSA)calculations reflect that both the compounds possess high inhibiting potential against SARS-CoV-2 including the recently emerged Omicron variant (B.1.1.529). CONCLUSION: Overall our study imparts the usage of phytochemicals as antiviral agents for SARS-CoV-2 infection. Additional in vitro and in vivo testing of these phytochemicals is required to confirm their potency.

Genetic predisposition of TNFα gene polymorphism in South-Indian Migraineurs and meta-analysis.

Migraine (Mg) is a multifaceted neurovascular disorder caused by genetic and several environmental etiologies. We have implemented a case-control study of TNFα gene polymorphism in 212 Mg patients and 218 healthy controls utilizing the ARMS-PCR technique, followed by Sanger sequencing. Besides, we have conducted a meta-analysis of different genetic models (five genetic models) to combine and summarize the available data from 11 studies (including this present research). The strength of genetic associations in the meta-analysis used to assess by the pooled odds ratio (OR) and 95% confidence intervals (CI). The results of this case-control study discovered a significant relationship with Mg in recessive and homozygous genotype with OR = 2.35 (95% CI [0.96-5.74]), p-value = 0.045. Also, the outcomes of meta-analysis suggested an irrelevant relationship between TNFα gene (rs1800629) polymorphism and Mg susceptibility in the five genetic models. However, subgrouping based on ethnic background showed a significant association in the allelic genetic model with OR = 1.53 (95% CI [1.02-2.31]), p = 0.040 respectively. The meta-analysis results of TNFα gene polymorphism may represent a risk factor for Mg among Asians. In the future, large scale, multicentric case-control study by classification of patients with Mg with or without aura can be performed worldwide to identify the potential genetic risk factors leading to Mg pathogenesis.

Association of leucine-rich repeat kinase 2 gene rs10878307 polymorphism and Parkinson's disease risk in South India-A meta-analysis and molecular dynamics simulation.

Communicated by Ramaswamy H. Sarma.

Influence of KCNJ11 gene polymorphism in T2DM of south Indian population.

Type-2 Diabetes mellitus (T2DM) is a complex metabolic disease. A case-control study was conducted with 218 T2DM and 214 controls to evaluate the T2DM risk of rs5219 polymorphism in the south Indian population. The analysis of allelic and genotype data showed a significant association of rs5219 polymorphism towards an increased risk of T2DM compared to controls with an odds ratio (OR) of 2.52, confidence interval (CI) (0.96-6.64) and p-value 0.046. The functional influence of rs5219 was tested which showed a significant correlation with HbA1c and serum uric acid levels. Although our results confirm rs5219 is a potential contributor to T2DM, several inconclusive results were noticed across the literature. Hence, the meta-analysis was performed by combining the results of case-control study with previous literature to confirm the rs5219 association with T2DM across various populations. Our meta-analysis revealed a significant risk association of rs5219 in T2DM under five genetic models. In summary, our analysis suggests, rs5219 polymorphism plays a significant role in T2DM susceptibility. Further, studies need to be conducted to determine the influence of rs5219 on the other characteristics of T2DM.

Metabolic profiling of Parkinson's disease: evidence of biomarker from gene expression analysis and rapid neural network detection.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder. The diagnosis of Parkinsonism is challenging because currently none of the clinical tests have been proven to help in diagnosis. PD may produce characteristic perturbations in the metabolome and such variations can be used as the marker for detection of disease. To test this hypothesis, we used proton NMR and multivariate analysis followed by neural network pattern detection. METHODS & RESULTS: 1H nuclear magnetic resonance spectroscopy analysis was carried out on plasma samples of 37 healthy controls and 43 drug-naive patients with PD. Focus on 22 targeted metabolites, 17 were decreased and 5 were elevated in PD patients (p < 0.05). Partial least squares discriminant analysis (PLS-DA) showed that pyruvate is the key metabolite, which contributes to the separation of PD from control samples. Furthermore, gene expression analysis shows significant (p < 0.05) change in expression of PDHB and NPFF genes leading to increased pyruvate concentration in blood plasma. Moreover, the implementation of 1H- NMR spectral pattern in neural network algorithm shows 97.14% accuracy in the detection of disease progression. CONCLUSION: The results increase the prospect of a robust molecular definition in detection of PD through the early symptomatic phase of the disease. This is an ultimate opening for therapeutic intervention. If validated in a genuinely prospective fashion in larger samples, the biomarker trajectories described here will go a long way to facilitate the development of useful therapies. Moreover, implementation of neural network will be a breakthrough in clinical screening and rapid detection of PD.

Genetic predisposition of IL-10 promoter polymorphisms with risk of multiple sclerosis: A meta-analysis.

Interleukin-10 (IL-10) is a anti-inflammatory cytokine, which controls inflammation by inhibiting the synthesis of several cytokines produced by Th1 cells and macrophages. The association between Interleukin-10 promoter polymorphisms with the risk of multiple sclerosis (MS) remains inconclusive. In this study, a meta-analysis has been performed to assess the relationship between IL-10 gene polymorphisms rs1800896, rs1800871 and rs1800872 with the risk of MS. Nine case-control studies were selected involving 2755 participants. The association between the polymorphisms and MS was examined by the pooled odds ratios (ORs) with 95% confidence intervals (CIs) in allelic, homozygote, heterozygote, dominant and recessive genetic models. Of analyzed genetic models, the pooled ORs and CIs of each SNPs calculated based on random (I2>50) or fixed effects (I2<50) methods, which showed no significant association (p-value>0.05) of genetic predisposition with MS susceptibility across Asian and Caucasian populations. In addition, assessment based on funnel plot and Egger's linear regression test suggests no publication bias in all analyzed genetic models. Overall, our results demonstrated that rs1800896, rs1800871 and rs1800872 polymorphisms may not be the risk factor for the development of MS in both the populations.

Association between PPARgammars1801282 polymorphism with diabetic nephropathy and type-2 diabetes mellitus susceptibility in south India and a meta-analysis / Asociación entre el polimorfismo rs1801282 de PPAR con nefropatía diabética y sensibilidad a la diabetes mellitus de tipo 2 en el sur de India y un metaanálisis

ANTECEDENTES: La nefropatía diabética (ND) es una complicación importante de la diabetes mellitus de tipo 2 (DMT2) con altas tasas de morbilidad mundial. OBJETIVO: Determinar la asociación del polimorfismo rs1801282 de PPAR en la DMT2 y la ND en la población del sur de India. MÉTODOS: Hemos llevado a cabo un estudio de casos y controles para analizar la asociación del polimorfismo rs1801282 con la DMT2 y la ND en 424 sujetos (ND = 128; DMT2 = 148 y controles = 148) pertenecientes a la población del sur de India mediante RCP-ARMS y método de secuenciación de Sanger. Además, se realizó un metaanálisis para el polimorfismo de rs1801282 a partir de la literatura publicada en varias bases de datos electrónicas para determinar la sensibilidad entre la DMT2 y la ND en varias poblaciones étnicas con 5 modelos genéticos. RESULTADOS: El genotipado de polimorfismo rs1801282 demostró una asociación significativa (valor de p < 0,05) con la ND y la DMT2 en comparación con los controles. En el metaanálisis no se observó asociación significativa (valor de p > 0,05) de rs1801282 con la ND frente a los controles en modelos genéticos homocigóticos, heterocigóticos, alélicos, recesivos y dominantes. Sin embargo, se observó una asociación significativa entre el polimorfismo de nucleótido único (PNU) rs1801282 SNP y la DMT2 en el modelo genético heterocigótico (Jj frente a JJ) con OR = 0,56, (IC del 95%: 0,43-0,74; p ≤ 0,0001 de poblaciones asiáticas y caucásicas. CONCLUSIÓN: El análisis general sugiere que el polimorfismo rs1801282 puede asociarse a ND y a DMT2. Se precisan más estudios de casos y controles sobre el gen PPAR con un taman˜ o de la muestra mayor que incluya todos los factores de confusión para corroborar los resultados de este metaanálisis

BACKGROUND: Diabetic Nephropathy (DN) is a major complication of Type 2 Diabetes Mellitus (T2DM) with high morbidity rates worldwide. OBJECTIVE: To determine the association of PPAR rs1801282 polymorphism in T2DM and DN in south Indian population. METHODS: We have conducted a case-control study to test the association of rs1801282 polymorphism with T2DM and DN in 424 subjects (DN = 128; T2DM = 148 and controls = 148) belonging to the south Indian population using ARMS-PCR and Sanger sequencing method. Further, a meta-analysis was performed for rs1801282 polymorphism from the published literature retrieved from various electronic databases to determine the susceptibility among T2DM and DN across various ethnic populations under five genetic models. RESULTS: The genotyping of rs1801282 polymorphism showed significant (p-value < 0.05) association with DN and T2DM compared to controls. In the meta-analysis, no significant association (p-value > 0.05) was noticed for rs1801282 with DN vs. controls in homozygote, heterozygote, allelic, recessive and dominant genetic models. However, a significant association was observed between rs1801282 SNP and T2DM under heterozygote (Jj vs JJ) genetic model with OR = 0.56, (95%CI [0.43-0.74]), p ≤ 0.0001 of Asian and Caucasian populations. CONCLUSION: Overall analysis suggests that the rs1801282 polymorphism might be associated with DN and T2DM. More case-control studies on the PPAR gene with a larger sample size including all the confounding factors are required to corroborate the findings from this meta-analysis