Jagarlapudi A R P Sarma | GVKBIO (original) (raw)

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Papers by Jagarlapudi A R P Sarma

Bioinformation, 2012

In this study, chemical feature based pharmacophore models of MMP-1, MMP-8 and MMP-13 inhibitors ... more In this study, chemical feature based pharmacophore models of MMP-1, MMP-8 and MMP-13 inhibitors have been developed with the aid of HypoGen module within Catalyst program package. In MMP-1 and MMP-13, all the compounds in the training set mapped HBA and RA, while in MMP-8, the training set mapped HBA and HY. These features revealed responsibility for the high molecular bioactivity, and this is further used as a three dimensional query to screen the knowledge based designed molecules. These pharmacophore models for collagenases picked up some potent and novel inhibitors. Subsequently, docking studies were performed for the potent molecules and novel hits were suggested for further studies based on the docking score and active site interactions in MMP-1, MMP-8 and MMP-13.

Journal of Catalysis, 1994

Computational Biology and Chemistry, 2019

Fragment based drug discovery used to screen for CSF1R inhibitors Indolylthiazolidne, Indolylbabr... more Fragment based drug discovery used to screen for CSF1R inhibitors Indolylthiazolidne, Indolylbabrbituric acid and Indolylchromes have been custom synthesized based on the rational analysis. In vitro kinase using fluorescence resonance energy transfer has revealed CSF1R kinase inhibition by compound 4a (a nitroindole). Predicted druggable properties such as TPSA, NPR analysis have been calculated to draw further insights that revealed that the identified nitroindole compound can cross Blood brain barrier.

Current Topics in Medicinal Chemistry, 2014

Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in ... more Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in angiogenesis, embryonic development, cell proliferation, cell differentiation, and wound healing. The FGFR isoforms and their receptors (FGFRs) considered as a potential targets and under intense research to design potential anticancer agents. Fibroblast growth factors (FGF's) and its growth factor receptors (FGFR) plays vital role in one of the critical pathway in monitoring angiogenesis. In the current study, quantitative pharmacophore models were generated and validated using known FGFR1 inhibitors. The pharmacophore models were generated using a set of 28 compounds (training). The top pharmacophore model was selected and validated using a set of 126 compounds (test set) and also using external validation. The validated pharmacophore was considered as a virtual screening query to screen a database of 400,000 virtual molecules and pharmacophore model retrieved 2800 hits. The retrieved hits were subsequently filtered based on the fit value. The selected hits were subjected for docking studies to observe the binding modes of the retrieved hits and also to reduce the false positives. One of the potential hits (thiazole-2-amine derivative) was selected based the pharmacophore fit value, dock score, and synthetic feasibility. A few analogues of the thiazole-2-amine derivative were synthesized. These compounds were screened for FGFR1 activity and anti-proliferative studies. The top active compound showed 56.87% inhibition of FGFR1 activity at 50 µM and also showed good cellular activity. Further optimization of thiazole-2-amine derivatives is in progress.

CSF-1R is a member of the class III receptor tyrosine kinases, along with c-Kit, Flt3, and PDGFR ... more CSF-1R is a member of the class III receptor tyrosine kinases, along with c-Kit, Flt3, and PDGFR α and β. Colony stimulatory factor 1 (CSF-1), also known as macrophage/monocyte colony stimulatory factor (M-CSF), binds to CSF-1R, resulting in dimerization, autophosphorylation, and activation of signal transduction. To identify potent inhibitors against CSF-1R we deployed rational approaches of drug discovery. In current study, pharmacophore models were generated using a set of 118 structurally diverse compounds out of which 19 were chosen as training set and 99 as test set with an inhibitory activity ranging from 0.4 to 2100 ηM . The model was further validated using a test set of 99 compounds and got a correlation of 0.75. Virtual screening was performed using validated pharmacophore query against inhouse database of 20,000 compounds. Docking analysis was performed for a set of virtual hits with high predictive activity and structural diversity using Glide. Docking was performed in ...

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed fo... more Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed for 77 pyrido(2,3-d)pyrimidines derivatives, inhibiting fibroblast growth factor receptor 1 (FGFR1). The QSAR model was developed using 56 compounds and its predictive ability was assessed using a test set of 21 compounds. The predictive 3D-QSAR models have conventional r 2 values of 0.920 for MFA and the cross-validated coefficient r 2 cv values of 0.884 for MFA. The results of 3D-QSAR methodologies provide a powerful tool directed to the design of potent and selective pyrido(2,3-d)pyrimidines inhibitors.

Tetrahedron Letters, 1989

International Journal of Bioscience, Biochemistry and Bioinformatics, 2011

Journal of Molecular Graphics and Modelling, 2010

European Journal of Medicinal Chemistry, 2011

The purpose of this study is to identify novel and potent inhibitors against HIV-1 reverse transc... more The purpose of this study is to identify novel and potent inhibitors against HIV-1 reverse transcriptase (RT). The crystal structure of the most active ligand was converted into a feature-shaped query. This query was used to align molecules to generate statistically valid 3D-QSAR (r(2) = 0.873) and Pharmacophore models (HypoGen). The best HypoGen model consists of three Pharmacophore features (one hydrogen bond acceptor, one hydrophobic aliphatic and one ring aromatic) and further validated using known RT inhibitors. The designed novel inhibitors are further subjected to docking studies to reduce the number of false positives. We have identified and proposed some novel and potential lead molecules as reverse transcriptase inhibitors using analog and structure based studies.

European Journal of Medicinal Chemistry, 2009

The best ZAP-70 inhibitor model consists of four-pharmacophore features, (1) one hydrogen bond ac... more The best ZAP-70 inhibitor model consists of four-pharmacophore features, (1) one hydrogen bond acceptor, (2) one hydrogen bond donor (3) one hydrophobic aliphatic and (4) one hydrophobic aromatic features. This model was validated against 110 known ZAP-70 inhibitors with a correlation of 0.902 as well as enrichment factor of 1.61 against a maximum value of 2. This model picked 4094 hits from a database of 238,819 molecules while 358 molecules were indicated as highly active. Subsequently, docking studies were performed on the hits and novel series of potent leads were suggested based on the interactions energy between ZAP-70 and the putative inhibitors which validated not only the virtual screening potential of the model but also identified the possible new Chemotypes.

Bioorganic & Medicinal Chemistry Letters, 2010

Inhibitors of the 5-Lipoxygenase (5-LOX) pathway have a therapeutic potential in a variety of inf... more Inhibitors of the 5-Lipoxygenase (5-LOX) pathway have a therapeutic potential in a variety of inflammatory disorders such as asthma. In this study, chemical feature based pharmacophore models of inhibitors of 5-LOX have been developed with the aid of HipHop and HypoGen modules within Catalyst program package. The best quantitative pharmacophore model, Hypo1, which has the highest correlation coefficient (0.97), consists

Acta Crystallographica Section E Structure Reports Online, 2009

Journal of cheminformatics, 2011

Since the classic Hopkins and Groom druggable genome review in 2002, there have been a number of ... more Since the classic Hopkins and Groom druggable genome review in 2002, there have been a number of publications updating both the hypothetical and successful human drug target statistics. However, listings of research targets that define the area between these two extremes are sparse because of the challenges of collating published information at the necessary scale. We have addressed this by interrogating databases, populated by expert curation, of bioactivity data extracted from patents and journal papers over the last 30 years.

Selective cyclooxygenase inhibitors have attracted much attention in recent times in the design o... more Selective cyclooxygenase inhibitors have attracted much attention in recent times in the design of new non-steroidal anti-inflammatory drugs (NSAID). 3D-QSAR studies have been performed on a series of 1,5-diarylpyrazoles that act as selective cyclooxygenase2 (COX-2) inhibitors, using three different methods: comparative molecular field analysis (CoMFA) with partial least squares (PLS) fit; molecular field analysis (MFA) and; receptor surface analysis (RSA) with genetic function algorithms (GFA). The analyses were carried out on 30 analogues of which 25 were used in the training set and the rest considered for the test set. These studies produced reasonably good predictive models with high cross-validated and conventional r values in all the three cases.

Journal of the Chemical Society, Perkin Transactions 2, 1987

Bioinformation, 2012

In this study, chemical feature based pharmacophore models of MMP-1, MMP-8 and MMP-13 inhibitors ... more In this study, chemical feature based pharmacophore models of MMP-1, MMP-8 and MMP-13 inhibitors have been developed with the aid of HypoGen module within Catalyst program package. In MMP-1 and MMP-13, all the compounds in the training set mapped HBA and RA, while in MMP-8, the training set mapped HBA and HY. These features revealed responsibility for the high molecular bioactivity, and this is further used as a three dimensional query to screen the knowledge based designed molecules. These pharmacophore models for collagenases picked up some potent and novel inhibitors. Subsequently, docking studies were performed for the potent molecules and novel hits were suggested for further studies based on the docking score and active site interactions in MMP-1, MMP-8 and MMP-13.

Journal of Catalysis, 1994

Computational Biology and Chemistry, 2019

Fragment based drug discovery used to screen for CSF1R inhibitors Indolylthiazolidne, Indolylbabr... more Fragment based drug discovery used to screen for CSF1R inhibitors Indolylthiazolidne, Indolylbabrbituric acid and Indolylchromes have been custom synthesized based on the rational analysis. In vitro kinase using fluorescence resonance energy transfer has revealed CSF1R kinase inhibition by compound 4a (a nitroindole). Predicted druggable properties such as TPSA, NPR analysis have been calculated to draw further insights that revealed that the identified nitroindole compound can cross Blood brain barrier.

Current Topics in Medicinal Chemistry, 2014

Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in ... more Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in angiogenesis, embryonic development, cell proliferation, cell differentiation, and wound healing. The FGFR isoforms and their receptors (FGFRs) considered as a potential targets and under intense research to design potential anticancer agents. Fibroblast growth factors (FGF's) and its growth factor receptors (FGFR) plays vital role in one of the critical pathway in monitoring angiogenesis. In the current study, quantitative pharmacophore models were generated and validated using known FGFR1 inhibitors. The pharmacophore models were generated using a set of 28 compounds (training). The top pharmacophore model was selected and validated using a set of 126 compounds (test set) and also using external validation. The validated pharmacophore was considered as a virtual screening query to screen a database of 400,000 virtual molecules and pharmacophore model retrieved 2800 hits. The retrieved hits were subsequently filtered based on the fit value. The selected hits were subjected for docking studies to observe the binding modes of the retrieved hits and also to reduce the false positives. One of the potential hits (thiazole-2-amine derivative) was selected based the pharmacophore fit value, dock score, and synthetic feasibility. A few analogues of the thiazole-2-amine derivative were synthesized. These compounds were screened for FGFR1 activity and anti-proliferative studies. The top active compound showed 56.87% inhibition of FGFR1 activity at 50 µM and also showed good cellular activity. Further optimization of thiazole-2-amine derivatives is in progress.

CSF-1R is a member of the class III receptor tyrosine kinases, along with c-Kit, Flt3, and PDGFR ... more CSF-1R is a member of the class III receptor tyrosine kinases, along with c-Kit, Flt3, and PDGFR α and β. Colony stimulatory factor 1 (CSF-1), also known as macrophage/monocyte colony stimulatory factor (M-CSF), binds to CSF-1R, resulting in dimerization, autophosphorylation, and activation of signal transduction. To identify potent inhibitors against CSF-1R we deployed rational approaches of drug discovery. In current study, pharmacophore models were generated using a set of 118 structurally diverse compounds out of which 19 were chosen as training set and 99 as test set with an inhibitory activity ranging from 0.4 to 2100 ηM . The model was further validated using a test set of 99 compounds and got a correlation of 0.75. Virtual screening was performed using validated pharmacophore query against inhouse database of 20,000 compounds. Docking analysis was performed for a set of virtual hits with high predictive activity and structural diversity using Glide. Docking was performed in ...

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed fo... more Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed for 77 pyrido(2,3-d)pyrimidines derivatives, inhibiting fibroblast growth factor receptor 1 (FGFR1). The QSAR model was developed using 56 compounds and its predictive ability was assessed using a test set of 21 compounds. The predictive 3D-QSAR models have conventional r 2 values of 0.920 for MFA and the cross-validated coefficient r 2 cv values of 0.884 for MFA. The results of 3D-QSAR methodologies provide a powerful tool directed to the design of potent and selective pyrido(2,3-d)pyrimidines inhibitors.

Tetrahedron Letters, 1989

International Journal of Bioscience, Biochemistry and Bioinformatics, 2011

Journal of Molecular Graphics and Modelling, 2010

European Journal of Medicinal Chemistry, 2011

The purpose of this study is to identify novel and potent inhibitors against HIV-1 reverse transc... more The purpose of this study is to identify novel and potent inhibitors against HIV-1 reverse transcriptase (RT). The crystal structure of the most active ligand was converted into a feature-shaped query. This query was used to align molecules to generate statistically valid 3D-QSAR (r(2) = 0.873) and Pharmacophore models (HypoGen). The best HypoGen model consists of three Pharmacophore features (one hydrogen bond acceptor, one hydrophobic aliphatic and one ring aromatic) and further validated using known RT inhibitors. The designed novel inhibitors are further subjected to docking studies to reduce the number of false positives. We have identified and proposed some novel and potential lead molecules as reverse transcriptase inhibitors using analog and structure based studies.

European Journal of Medicinal Chemistry, 2009

The best ZAP-70 inhibitor model consists of four-pharmacophore features, (1) one hydrogen bond ac... more The best ZAP-70 inhibitor model consists of four-pharmacophore features, (1) one hydrogen bond acceptor, (2) one hydrogen bond donor (3) one hydrophobic aliphatic and (4) one hydrophobic aromatic features. This model was validated against 110 known ZAP-70 inhibitors with a correlation of 0.902 as well as enrichment factor of 1.61 against a maximum value of 2. This model picked 4094 hits from a database of 238,819 molecules while 358 molecules were indicated as highly active. Subsequently, docking studies were performed on the hits and novel series of potent leads were suggested based on the interactions energy between ZAP-70 and the putative inhibitors which validated not only the virtual screening potential of the model but also identified the possible new Chemotypes.

Bioorganic & Medicinal Chemistry Letters, 2010

Inhibitors of the 5-Lipoxygenase (5-LOX) pathway have a therapeutic potential in a variety of inf... more Inhibitors of the 5-Lipoxygenase (5-LOX) pathway have a therapeutic potential in a variety of inflammatory disorders such as asthma. In this study, chemical feature based pharmacophore models of inhibitors of 5-LOX have been developed with the aid of HipHop and HypoGen modules within Catalyst program package. The best quantitative pharmacophore model, Hypo1, which has the highest correlation coefficient (0.97), consists

Acta Crystallographica Section E Structure Reports Online, 2009

Journal of cheminformatics, 2011

Since the classic Hopkins and Groom druggable genome review in 2002, there have been a number of ... more Since the classic Hopkins and Groom druggable genome review in 2002, there have been a number of publications updating both the hypothetical and successful human drug target statistics. However, listings of research targets that define the area between these two extremes are sparse because of the challenges of collating published information at the necessary scale. We have addressed this by interrogating databases, populated by expert curation, of bioactivity data extracted from patents and journal papers over the last 30 years.

Selective cyclooxygenase inhibitors have attracted much attention in recent times in the design o... more Selective cyclooxygenase inhibitors have attracted much attention in recent times in the design of new non-steroidal anti-inflammatory drugs (NSAID). 3D-QSAR studies have been performed on a series of 1,5-diarylpyrazoles that act as selective cyclooxygenase2 (COX-2) inhibitors, using three different methods: comparative molecular field analysis (CoMFA) with partial least squares (PLS) fit; molecular field analysis (MFA) and; receptor surface analysis (RSA) with genetic function algorithms (GFA). The analyses were carried out on 30 analogues of which 25 were used in the training set and the rest considered for the test set. These studies produced reasonably good predictive models with high cross-validated and conventional r values in all the three cases.

Journal of the Chemical Society, Perkin Transactions 2, 1987