Srivani Palukuri - Academia.edu (original) (raw)
Papers by Srivani Palukuri
Chemical Biology & Drug Design, 2011
In this present study, three-dimensional quantitative structure−activity relationship (3D-QSAR) a... more In this present study, three-dimensional quantitative structure−activity relationship (3D-QSAR) and 2D-QSAR analyses were performed on the series of compounds Hepatitis C Virus NS5B polymerase inhibitors using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and stepwise multiple linear regression (SW-MLR) approaches. A CoMFA model with good predictive ability was generated based on training set of 39 compounds and showed satisfactory statistical results (q 2 = 0.600, r 2 = 0.871). To improve the contribution of points for next analyses, CoMFA (after region focusing) was employed in biases of similar alignment and showed appropriate predictive results (q 2 = 0.691, r 2 = 0.889). A reliable CoMSIA model out of 31 different combinations with the higher "leave-one-out'" crossvalidation correlation coefficients (q 2) were obtained and indicated suitable statistical results (q 2 = 0.664, r 2 = 0.911). An external test set of nine compounds were used to evaluate the predictive ability of generated models. The 2D-QSAR model was built with the four descriptors selected by stepwise technique and presented high predictive ability (R train 2 = 0.833, R test 2 = 0.773, Q LOO 2 = 0.758, Q BOOT 2 = 0.736). The derived contour maps from each model were assessed to identify the significant structural features required for improving biological activity so as to design potent HCV NS5B polymerase inhibitors.
Diabetes, 2021
Introduction: Use of Digital therapeutics can act as a valuable tool enabling more personalized c... more Introduction: Use of Digital therapeutics can act as a valuable tool enabling more personalized care among diabetics. The Breathe Diabetes Management Program (BDMP) delivers personalized interventions encouraging them to track their blood glucose level, weight, and physical activity. Objective: To assess BDMP app in type 2 diabetics in achieving healthy outcomes in Indian population. Methodology: The group of participants (N=181, A1C >6.5%) was divided into 3 groups - (1) patients treated with the BDMP plus Doctor-prescribed medication (n=60), (2) patients treated with the BDMP plus Doctor-prescribed medication plus Stress Reduction module (n=61) and (3) patients only taking the Doctor-prescribed medication (control group with n=60). Results: At the end of the 16 weeks, patients from Group 1 showed 81.6% program completion rate, 46.01% program adherence, an average of 5.64% of baseline body weight loss, an average of 0.68% reduction in A1C and Penn State Worry Questionnaire (PSWQ...
Diabetes, 2021
Background: Nonalcoholic fatty liver disease (NAFLD) is present in the body with metabolic disord... more Background: Nonalcoholic fatty liver disease (NAFLD) is present in the body with metabolic disorders such as type 2 diabetes mellitus (T2DM), obesity, and cardiovascular disease. However, no significant evidence has been found till date exhibiting their association epidemiologically in Indian patients. Objective: To assess the association among NAFLD, T2DM, and obesity, and to validate the scoring system with grades of fatty liver (severity of liver disease) estimated by ultrasound vs. NAFLD fibrosis score, BARD score, and APRI score. Methodology: A retrospective, observational study was conducted out in patients with NAFLD (n=316) where diagnosis and grades of fatty liver were established via ultrasound reports. The patients were divided into two groups, Group A (n=114, NAFLD with T2DM) and Group B (n=202, NAFLD without T2DM). R 4.0.0 was used for statistical analysis. Results: The mean age (in years) of the patients was 54.08 ± 10.78 in Group A and 48.10 ± 15.36 in Group B. The me...
Exclusive Real World Evidence Journal, 2021
Objective: To compare and validate the calculated LDL values from Friedewald and Anandaraja formu... more Objective: To compare and validate the calculated LDL values from Friedewald and Anandaraja formulas with directly measured values in the Indian population. Material and Methods: The study was conducted on randomly selected 102 individuals of 16 to 88 years of age during December 2019. The direct LDL values were measured using selective solubilization assay, and Friedewald and Anandaraja formulas were used to calculate LDL for comparison. The correlations between direct and calculated methods were assessed using the linear regression method. Receiver operating characteristic analysis with nonparametric distribution was used to compare the sensitivity and specificity of the three methods. Results: The average LDL of direct method, 107.3 mg/dL, Friedewald formula, 89.7 mg/dL, and Anandaraja was 99.0 mg/dL. The relation between direct and calculated values assessed by linear regression showed 97% and 87% of correlation with Friedewald and Anandaraja, respectively. The ROC analysis infe...
Exclusive Real World Evidence Journal, 2021
Objective: To study the association between ankle brachial index (ABI) and microvascular complica... more Objective: To study the association between ankle brachial index (ABI) and microvascular complications in Type 2 diabetes (T2DM) patients with the coronary arterial disease (CAD). Methodology: A retrospective study was carried out on 3,458 T2DM patients reportedly with CAD, G1 (n=33), and without CAD, G2 (n=3125), who had given the ABI test. ABI was defined as normal (1.0 - 1.4) and abnormal (<1.0 and >1.4). The logistic regression analysis was used to identify the determinants of CAD positive outcomes in T2DM patients. Results: Overall, patient percentage-wise CAD 10% (333), abnormal ABI 26% (913), neuropathy 37% (1278), nephropathy, 8% (293), and retinopathy <1% (24). The ABI abnormality and CAD positives were higher in patients with nephropathy (32 and 20%) than in neuropathy (28 and 13%). Age-wise, 52 and 62% of neuropathy and nephropathy patients, respectively, were >60 years and had shown increased ABI abnormality from age 50 years onwards. The logistic model had s...
Diabetes, 2020
Introduction: Since many new diabetic medications are costly and often have side effects, quick f... more Introduction: Since many new diabetic medications are costly and often have side effects, quick feedback would allow for timely decisions. The current study present the role of CGM in titrate medication to achieve glycemic target of diabetes mellitus patients using 14 days CGM report (AGP). Methodology: Retrospective AGP of 214 patients was collected from 2017 to 2019. Target glucose range was considered as 70-180 mg/dL, hypoglycemia was categorized as low (54-69 mg/dL) and very low (<54 mg/dL) and hyperglycemia as high (180-250 mg/dL) and very high (>250 mg/dL). The % of time a patient spent in above ranges was illustrated as time in target range (TIR), time below range (TBR), and time above range (TAR), respectively. The glycemic variability (GV) parameters included standard deviation (SD) and coefficient of variation (CV). Changes in diabetic medications were done, if required, after first week of CGM. Variation in TIR, TAR, TBR and CV were analyzed before (first week) and ...
Diabetes, 2020
Objective: To study the association between ankle brachial index (ABI) and microvascular complica... more Objective: To study the association between ankle brachial index (ABI) and microvascular complications in type 2 diabetes (T2DM) patients with coronary arterial disease (CAD). Methodology: A retrospective study was carried on 3,468 T2DM patients who gave ABI test between 2002 and 2019. ABI status was defined as normal (1.0-1.4) and abnormal (<1.0 and >1.4). The distribution of patients was given in percentages. The logistic regression was used to study ABI status, microvascular complications and CAD risk factors (hypertension, age, BMI, smoking etc) role on CAD, and the resulted odds ratio (OR) was given with 95% CI and p-value. Results: Patients were classified based on history of CAD, with, G1 (334), and without, G2 (3134). In G1, 69% patients were normal ABI and 31% abnormal. Across G1 and G2, neuropathy was populated with 37% (1279), nephropathy, 8% (293), hypertension, 15% (507) and hypothyroidism, 8% (270). The ABI abnormality was high in nephropathy (G1: 41%; G2: 29%) t...
Journal of Molecular Modeling, 2010
Structure and analog based analysis of 3D-QSAR, CoMFA and CoMSIA, along with different docking pr... more Structure and analog based analysis of 3D-QSAR, CoMFA and CoMSIA, along with different docking protocols were used to evaluate the structure activity relationship of 26 analogues of 1-aryl sulfamido-2-alkyl piperazines to model the activities of group I and II secreted phospholipases A 2 (sPLA 2 s) and probe into the chemical space and nature of receptorligand interactions. The best CoMFA model yields cross-validated (q 2) and conventional correlation coefficients (r 2) of 0.703 and 0.962 respectively whereas CoMSIA model yields q 2 and r 2 values of 0.408 and 0.922 respectively, followed by docking analysis using FlexX and GOLD methodologies on the X-ray structure of human and bovine PLA 2 s. A comparative study was made to find out the differences in the active site residues of both PLA 2 s. The information enunciated from the analysis of CoMFA and CoMSIA maps and docking results were analyzed and employed in the design of 29 new ligands using molecules 4, 21, 22 from the initial set as templates. New ligands for group I and II secreted phospholipases A 2 (sPLA 2 s) have been thus designed based on the 32 analogues of 1-aryl sulfamido-2-alkyl piperazine with a cursory note on its synthetic feasibility. Molecular modeling studies indicate that the newly designed ligands are expected to show high affinity and experimental efforts in this direction is highly rewarding.
Journal of Molecular Graphics and Modelling, 2009
Choline kinase (ChoK) is reported to involve in cell signaling pathways and cell growth by regula... more Choline kinase (ChoK) is reported to involve in cell signaling pathways and cell growth by regulating the intermediate, phosphocholine (PCho), which is the first step to biosynthesis a membrane phospholipid, phosphatidylcholine. The PCho levels are overexpressed due to elevated activation of the protein under carcinogenesis conditions. ChoK has thus evolved as a novel target for various cancers and a range of compounds has been reported in this course as potent ChoK inhibitors. However, not much information is known about the binding site of the inhibitors. Therefore, we ventured to unravel the possible binding site of 39 bis-quinolinium inhibitors from which the structural requirement for better protein-ligand complex was delved. Molecular docking and 3D-QSAR studies namely comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on the series. The knowledge of the active site was obtained from the site id search and molcad surface calculations of Sybyl, which was further considered for docking studies. In 3D-QSAR, the best predictions were obtained from the model where 29 compounds were considered in the training set and remaining 10 in the test set. The best CoMFA statistics were obtained with r 2 of 0.99 and q 2 of 0.81 while, CoMSIA was resulted with r 2 of 0.98 and q 2 of 0.77. A comparative analysis was done with the resulted 3D-QSAR maps and the docked poses by overlaying the maps on the active site residues. Since, there is no reported ligand co-crystallized structure of ChoK the present study provides valuable clues on the binding conformation of the ligand and its interactions with the active site.
Journal of Molecular Graphics and Modelling, 2007
Two-and three-dimensional quantitative structure-activity relationship (QSAR) and docking studies... more Two-and three-dimensional quantitative structure-activity relationship (QSAR) and docking studies were carried out on a series of pyridopurinones, to model their phosphodiesterase 5 (PDE5) inhibitory activities. 2D-QSAR was performed using the heuristic and best multi linear regression (BMLR) methods in CODESSA (comprehensive descriptors for structural and statistical analysis), which had given linear models between the inhibitory activity and five descriptors of PDE5 inhibitors, with r 2 = 0.987, 0.987, q 2 = 0.970, 0.970, F = 166.71, 166.71 and s 2 = 0.0004, 0.0176, respectively. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) have provided statistically significant models with q 2 values of 0.784, 0.742 and r 2 values of 0.975, 0.972 respectively. The predictive ability of the models was validated using a set of 6 compounds that were not included in the training set and the predictive r 2 obtained for the test set was 0.901 and 0.888 respectively. Docking studies were employed to determine the probable binding conformation of these analogues in the PDE5 active site using the programs GOLD and AutoDock whose results were found complementary with 3D-QSAR maps. Since the potency towards PDE5 and the selectivity over PDE6 is important for the successful development of new PDE5 inhibitors, a PDE6 homology model was built using Insight II and Modeller with Phi-Psi BLAST alignment. The molecules were docked in the active site of PDE6 and analyzed the probable reasons for selectivity of these molecules towards PDE5 over PDE6. Mapping the 3D-QSAR models to the active site of PDE5 provides a new insight into the protein-inhibitor interactions and helpful in designing potent and selective PDE5 inhibitors for the treatment of erectile dysfunction.
Journal of Computer-Aided Molecular Design, 2007
The p38 protein kinase is a serine-threonine mitogen activated protein kinase, which plays an imp... more The p38 protein kinase is a serine-threonine mitogen activated protein kinase, which plays an important role in inflammation and arthritis. A combined study of 3D-QSAR and molecular docking has been undertaken to explore the structural insights of pyrazolyl urea p38 kinase inhibitors. The 3D-QSAR studies involved comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA). The best CoMFA model was derived from the atom fit alignment with a cross-validated r 2 (q 2) value of 0.516 and conventional r 2 of 0.950, while the best CoMSIA model yielded a q 2 of 0.455 and r 2 of 0.979 (39 molecules in training set, 9 molecules in test set). The CoMFA and CoMSIA contour maps generated from these models provided inklings about the influence of interactive molecular fields in the space on the activity. GOLD, Sybyl (FlexX) and AutoDock docking protocols were exercised to explore the protein-inhibitor interactions. The integration of 3D-QSAR and molecular docking has proffered essential structural features of pyrazolyl urea inhibitors and also strategies to design new potent analogues with enhanced activity.
Journal of Chemical Theory and Computation, 2008
Current Pharmaceutical Design, 2008
Current Medicinal Chemistry, 2006
Chemical Biology & Drug Design, 2011
In this present study, three-dimensional quantitative structure−activity relationship (3D-QSAR) a... more In this present study, three-dimensional quantitative structure−activity relationship (3D-QSAR) and 2D-QSAR analyses were performed on the series of compounds Hepatitis C Virus NS5B polymerase inhibitors using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and stepwise multiple linear regression (SW-MLR) approaches. A CoMFA model with good predictive ability was generated based on training set of 39 compounds and showed satisfactory statistical results (q 2 = 0.600, r 2 = 0.871). To improve the contribution of points for next analyses, CoMFA (after region focusing) was employed in biases of similar alignment and showed appropriate predictive results (q 2 = 0.691, r 2 = 0.889). A reliable CoMSIA model out of 31 different combinations with the higher "leave-one-out'" crossvalidation correlation coefficients (q 2) were obtained and indicated suitable statistical results (q 2 = 0.664, r 2 = 0.911). An external test set of nine compounds were used to evaluate the predictive ability of generated models. The 2D-QSAR model was built with the four descriptors selected by stepwise technique and presented high predictive ability (R train 2 = 0.833, R test 2 = 0.773, Q LOO 2 = 0.758, Q BOOT 2 = 0.736). The derived contour maps from each model were assessed to identify the significant structural features required for improving biological activity so as to design potent HCV NS5B polymerase inhibitors.
Diabetes, 2021
Introduction: Use of Digital therapeutics can act as a valuable tool enabling more personalized c... more Introduction: Use of Digital therapeutics can act as a valuable tool enabling more personalized care among diabetics. The Breathe Diabetes Management Program (BDMP) delivers personalized interventions encouraging them to track their blood glucose level, weight, and physical activity. Objective: To assess BDMP app in type 2 diabetics in achieving healthy outcomes in Indian population. Methodology: The group of participants (N=181, A1C >6.5%) was divided into 3 groups - (1) patients treated with the BDMP plus Doctor-prescribed medication (n=60), (2) patients treated with the BDMP plus Doctor-prescribed medication plus Stress Reduction module (n=61) and (3) patients only taking the Doctor-prescribed medication (control group with n=60). Results: At the end of the 16 weeks, patients from Group 1 showed 81.6% program completion rate, 46.01% program adherence, an average of 5.64% of baseline body weight loss, an average of 0.68% reduction in A1C and Penn State Worry Questionnaire (PSWQ...
Diabetes, 2021
Background: Nonalcoholic fatty liver disease (NAFLD) is present in the body with metabolic disord... more Background: Nonalcoholic fatty liver disease (NAFLD) is present in the body with metabolic disorders such as type 2 diabetes mellitus (T2DM), obesity, and cardiovascular disease. However, no significant evidence has been found till date exhibiting their association epidemiologically in Indian patients. Objective: To assess the association among NAFLD, T2DM, and obesity, and to validate the scoring system with grades of fatty liver (severity of liver disease) estimated by ultrasound vs. NAFLD fibrosis score, BARD score, and APRI score. Methodology: A retrospective, observational study was conducted out in patients with NAFLD (n=316) where diagnosis and grades of fatty liver were established via ultrasound reports. The patients were divided into two groups, Group A (n=114, NAFLD with T2DM) and Group B (n=202, NAFLD without T2DM). R 4.0.0 was used for statistical analysis. Results: The mean age (in years) of the patients was 54.08 ± 10.78 in Group A and 48.10 ± 15.36 in Group B. The me...
Exclusive Real World Evidence Journal, 2021
Objective: To compare and validate the calculated LDL values from Friedewald and Anandaraja formu... more Objective: To compare and validate the calculated LDL values from Friedewald and Anandaraja formulas with directly measured values in the Indian population. Material and Methods: The study was conducted on randomly selected 102 individuals of 16 to 88 years of age during December 2019. The direct LDL values were measured using selective solubilization assay, and Friedewald and Anandaraja formulas were used to calculate LDL for comparison. The correlations between direct and calculated methods were assessed using the linear regression method. Receiver operating characteristic analysis with nonparametric distribution was used to compare the sensitivity and specificity of the three methods. Results: The average LDL of direct method, 107.3 mg/dL, Friedewald formula, 89.7 mg/dL, and Anandaraja was 99.0 mg/dL. The relation between direct and calculated values assessed by linear regression showed 97% and 87% of correlation with Friedewald and Anandaraja, respectively. The ROC analysis infe...
Exclusive Real World Evidence Journal, 2021
Objective: To study the association between ankle brachial index (ABI) and microvascular complica... more Objective: To study the association between ankle brachial index (ABI) and microvascular complications in Type 2 diabetes (T2DM) patients with the coronary arterial disease (CAD). Methodology: A retrospective study was carried out on 3,458 T2DM patients reportedly with CAD, G1 (n=33), and without CAD, G2 (n=3125), who had given the ABI test. ABI was defined as normal (1.0 - 1.4) and abnormal (<1.0 and >1.4). The logistic regression analysis was used to identify the determinants of CAD positive outcomes in T2DM patients. Results: Overall, patient percentage-wise CAD 10% (333), abnormal ABI 26% (913), neuropathy 37% (1278), nephropathy, 8% (293), and retinopathy <1% (24). The ABI abnormality and CAD positives were higher in patients with nephropathy (32 and 20%) than in neuropathy (28 and 13%). Age-wise, 52 and 62% of neuropathy and nephropathy patients, respectively, were >60 years and had shown increased ABI abnormality from age 50 years onwards. The logistic model had s...
Diabetes, 2020
Introduction: Since many new diabetic medications are costly and often have side effects, quick f... more Introduction: Since many new diabetic medications are costly and often have side effects, quick feedback would allow for timely decisions. The current study present the role of CGM in titrate medication to achieve glycemic target of diabetes mellitus patients using 14 days CGM report (AGP). Methodology: Retrospective AGP of 214 patients was collected from 2017 to 2019. Target glucose range was considered as 70-180 mg/dL, hypoglycemia was categorized as low (54-69 mg/dL) and very low (<54 mg/dL) and hyperglycemia as high (180-250 mg/dL) and very high (>250 mg/dL). The % of time a patient spent in above ranges was illustrated as time in target range (TIR), time below range (TBR), and time above range (TAR), respectively. The glycemic variability (GV) parameters included standard deviation (SD) and coefficient of variation (CV). Changes in diabetic medications were done, if required, after first week of CGM. Variation in TIR, TAR, TBR and CV were analyzed before (first week) and ...
Diabetes, 2020
Objective: To study the association between ankle brachial index (ABI) and microvascular complica... more Objective: To study the association between ankle brachial index (ABI) and microvascular complications in type 2 diabetes (T2DM) patients with coronary arterial disease (CAD). Methodology: A retrospective study was carried on 3,468 T2DM patients who gave ABI test between 2002 and 2019. ABI status was defined as normal (1.0-1.4) and abnormal (<1.0 and >1.4). The distribution of patients was given in percentages. The logistic regression was used to study ABI status, microvascular complications and CAD risk factors (hypertension, age, BMI, smoking etc) role on CAD, and the resulted odds ratio (OR) was given with 95% CI and p-value. Results: Patients were classified based on history of CAD, with, G1 (334), and without, G2 (3134). In G1, 69% patients were normal ABI and 31% abnormal. Across G1 and G2, neuropathy was populated with 37% (1279), nephropathy, 8% (293), hypertension, 15% (507) and hypothyroidism, 8% (270). The ABI abnormality was high in nephropathy (G1: 41%; G2: 29%) t...
Journal of Molecular Modeling, 2010
Structure and analog based analysis of 3D-QSAR, CoMFA and CoMSIA, along with different docking pr... more Structure and analog based analysis of 3D-QSAR, CoMFA and CoMSIA, along with different docking protocols were used to evaluate the structure activity relationship of 26 analogues of 1-aryl sulfamido-2-alkyl piperazines to model the activities of group I and II secreted phospholipases A 2 (sPLA 2 s) and probe into the chemical space and nature of receptorligand interactions. The best CoMFA model yields cross-validated (q 2) and conventional correlation coefficients (r 2) of 0.703 and 0.962 respectively whereas CoMSIA model yields q 2 and r 2 values of 0.408 and 0.922 respectively, followed by docking analysis using FlexX and GOLD methodologies on the X-ray structure of human and bovine PLA 2 s. A comparative study was made to find out the differences in the active site residues of both PLA 2 s. The information enunciated from the analysis of CoMFA and CoMSIA maps and docking results were analyzed and employed in the design of 29 new ligands using molecules 4, 21, 22 from the initial set as templates. New ligands for group I and II secreted phospholipases A 2 (sPLA 2 s) have been thus designed based on the 32 analogues of 1-aryl sulfamido-2-alkyl piperazine with a cursory note on its synthetic feasibility. Molecular modeling studies indicate that the newly designed ligands are expected to show high affinity and experimental efforts in this direction is highly rewarding.
Journal of Molecular Graphics and Modelling, 2009
Choline kinase (ChoK) is reported to involve in cell signaling pathways and cell growth by regula... more Choline kinase (ChoK) is reported to involve in cell signaling pathways and cell growth by regulating the intermediate, phosphocholine (PCho), which is the first step to biosynthesis a membrane phospholipid, phosphatidylcholine. The PCho levels are overexpressed due to elevated activation of the protein under carcinogenesis conditions. ChoK has thus evolved as a novel target for various cancers and a range of compounds has been reported in this course as potent ChoK inhibitors. However, not much information is known about the binding site of the inhibitors. Therefore, we ventured to unravel the possible binding site of 39 bis-quinolinium inhibitors from which the structural requirement for better protein-ligand complex was delved. Molecular docking and 3D-QSAR studies namely comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on the series. The knowledge of the active site was obtained from the site id search and molcad surface calculations of Sybyl, which was further considered for docking studies. In 3D-QSAR, the best predictions were obtained from the model where 29 compounds were considered in the training set and remaining 10 in the test set. The best CoMFA statistics were obtained with r 2 of 0.99 and q 2 of 0.81 while, CoMSIA was resulted with r 2 of 0.98 and q 2 of 0.77. A comparative analysis was done with the resulted 3D-QSAR maps and the docked poses by overlaying the maps on the active site residues. Since, there is no reported ligand co-crystallized structure of ChoK the present study provides valuable clues on the binding conformation of the ligand and its interactions with the active site.
Journal of Molecular Graphics and Modelling, 2007
Two-and three-dimensional quantitative structure-activity relationship (QSAR) and docking studies... more Two-and three-dimensional quantitative structure-activity relationship (QSAR) and docking studies were carried out on a series of pyridopurinones, to model their phosphodiesterase 5 (PDE5) inhibitory activities. 2D-QSAR was performed using the heuristic and best multi linear regression (BMLR) methods in CODESSA (comprehensive descriptors for structural and statistical analysis), which had given linear models between the inhibitory activity and five descriptors of PDE5 inhibitors, with r 2 = 0.987, 0.987, q 2 = 0.970, 0.970, F = 166.71, 166.71 and s 2 = 0.0004, 0.0176, respectively. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) have provided statistically significant models with q 2 values of 0.784, 0.742 and r 2 values of 0.975, 0.972 respectively. The predictive ability of the models was validated using a set of 6 compounds that were not included in the training set and the predictive r 2 obtained for the test set was 0.901 and 0.888 respectively. Docking studies were employed to determine the probable binding conformation of these analogues in the PDE5 active site using the programs GOLD and AutoDock whose results were found complementary with 3D-QSAR maps. Since the potency towards PDE5 and the selectivity over PDE6 is important for the successful development of new PDE5 inhibitors, a PDE6 homology model was built using Insight II and Modeller with Phi-Psi BLAST alignment. The molecules were docked in the active site of PDE6 and analyzed the probable reasons for selectivity of these molecules towards PDE5 over PDE6. Mapping the 3D-QSAR models to the active site of PDE5 provides a new insight into the protein-inhibitor interactions and helpful in designing potent and selective PDE5 inhibitors for the treatment of erectile dysfunction.
Journal of Computer-Aided Molecular Design, 2007
The p38 protein kinase is a serine-threonine mitogen activated protein kinase, which plays an imp... more The p38 protein kinase is a serine-threonine mitogen activated protein kinase, which plays an important role in inflammation and arthritis. A combined study of 3D-QSAR and molecular docking has been undertaken to explore the structural insights of pyrazolyl urea p38 kinase inhibitors. The 3D-QSAR studies involved comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA). The best CoMFA model was derived from the atom fit alignment with a cross-validated r 2 (q 2) value of 0.516 and conventional r 2 of 0.950, while the best CoMSIA model yielded a q 2 of 0.455 and r 2 of 0.979 (39 molecules in training set, 9 molecules in test set). The CoMFA and CoMSIA contour maps generated from these models provided inklings about the influence of interactive molecular fields in the space on the activity. GOLD, Sybyl (FlexX) and AutoDock docking protocols were exercised to explore the protein-inhibitor interactions. The integration of 3D-QSAR and molecular docking has proffered essential structural features of pyrazolyl urea inhibitors and also strategies to design new potent analogues with enhanced activity.
Journal of Chemical Theory and Computation, 2008
Current Pharmaceutical Design, 2008
Current Medicinal Chemistry, 2006