SRAVANI AKULA - Academia.edu (original) (raw)

Papers by SRAVANI AKULA

Research paper thumbnail of CCDC 1555220: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Research paper thumbnail of Computational Analysis of Epidermal Growth Factor Receptor Mutations Predicts Differential Drug Sensitivity Profiles toward Kinase Inhibitors

Journal of Thoracic Oncology, 2018

Introduction: A significant proportion of patients with lung cancer carry mutations in the EGFR k... more Introduction: A significant proportion of patients with lung cancer carry mutations in the EGFR kinase domain. The presence of a deletion mutation in exon 19 or L858R point mutation in the EGFR kinase domain has been shown to cause enhanced efficacy of inhibitor treatment in patients with NSCLC. Several less frequent (uncommon) mutations in the EGFR kinase domain with potential implications in treatment response have also been reported. The role of a limited number of uncommon mutations in drug sensitivity was experimentally verified. However, a huge number of these mutations remain uncharacterized for inhibitor sensitivity or resistance. Methods: A large-scale computational analysis of clinically reported 298 point mutants of EGFR kinase domain has been performed, and drug sensitivity profiles for each mutant toward seven kinase inhibitors has been determined by molecular docking. In addition, the relative inhibitor binding affinity toward each drug as compared with that of adenosine triphosphate was calculated for each mutant. Results: The inhibitor sensitivity profiles predicted in this study for a set of previously characterized mutants correlated well with the published clinical, experimental, and computational data. Both the single and compound mutations displayed differential inhibitor sensitivity toward firstand next-generation kinase inhibitors. Conclusions: The present study provides predicted drug sensitivity profiles for a large panel of uncommon EGFR mutations toward multiple inhibitors, which may help clinicians in deciding mutant-specific treatment strategies.

Research paper thumbnail of Consensus anticancer activity profiles derived from the meta-analysis of reference compounds for widely used cell lines

Future Medicinal Chemistry, 2018

Aim: To establish a standard reference for bioactivity of widely used anticancer compounds that m... more Aim: To establish a standard reference for bioactivity of widely used anticancer compounds that might be useful for meaningful interpretation of the cell viability data generated for novel synthetic derivatives. Materials & methods: Meta-analysis of published IC50 values was carried out for commonly used anticancer compounds and cell viability experiments were performed to validate the role of certain factors in drug activity. Results & conclusion: Variability in the published IC50 values was demonstrated. Based on median IC50 values derived from pooled published data, cell lines were classified as either sensitive or resistant. Further, factors that influence IC50 values were discussed, thus encouraging researchers to devise more rational experimental approaches to enhance the success rate in later stages of drug development.

Research paper thumbnail of Elucidation of conformational diversity of druggable enzymes and classification of chemical modulators based on inhibitor-bound structures

Journal of Biomolecular Structure and Dynamics, 2018

Proteins are remarkably flexible and exhibit multiple conformations each of which may be modulate... more Proteins are remarkably flexible and exhibit multiple conformations each of which may be modulated or stabilized by natural/synthetic ligands. Analysis of conformational diversity of an enzyme helps in understanding its function and has implications in biochemical and pharmacological applications. The variation observed among an array of structures of a particular enzyme can be indicative of its conformational diversity. In the present study, a large scale superposition analysis of enzyme-ligand co-crystal structures was performed revealing the presence of higher conformational diversity in the kinome A c c e p t e d M a n u s c r i p t than that of the non-kinome. In addition, a functional classification of chemical modulators (ligands) for each of the 149 druggable enzymes was performed based on the protein conformation they stabilized. The comprehensive functional classification of chemical modulators combined with the structural diversity profiling of druggable enzymes presented in this study may serve as a resource for chemical biology and drug development programs.

Research paper thumbnail of Computational analysis of ABL kinase mutations allows predicting drug sensitivity against selective kinase inhibitors

Tumor Biology, 2017

The ABL kinase inhibitor imatinib has been used as front-line therapy for Philadelphia-positive c... more The ABL kinase inhibitor imatinib has been used as front-line therapy for Philadelphia-positive chronic myeloid leukemia. However, a significant proportion of imatinib-treated patients relapse due to occurrence of mutations in the ABL kinase domain. Although inhibitor sensitivity for a set of mutations was reported, the role of less frequent ABL kinase mutations in drug sensitivity/resistance is not known. Moreover, recent reports indicate distinct resistance profiles for second-generation ABL inhibitors. We thus employed a computational approach to predict drug sensitivity of 234 point mutations that were reported in chronic myeloid leukemia patients. Initial validation analysis of our approach using a panel of previously studied frequent mutations indicated that the computational data generated in this study correlated well with the published experimental/clinical data. In addition, we present drug sensitivity profiles for remaining point mutations by computational docking analysi...

Research paper thumbnail of Silver-catalyzed synthesis of pyrrolopiperazine fused with oxazine/imidazole via a domino approach: evaluation of anti-cancer activity

New Journal of Chemistry, 2018

Ag-Catalyzed synthesis of pyrrolopiperazine fused with oxazine/imidazole by the reaction of δ-alk... more Ag-Catalyzed synthesis of pyrrolopiperazine fused with oxazine/imidazole by the reaction of δ-alkynyl aldehydes and nucleophilic amines was performed. Several of these compounds were found to exhibit anti-cancer activity against cancer cell lines.

Research paper thumbnail of Silver-catalyzed synthesis of pyrrolopiperazine fused with oxazine/imidazole via a domino approach: evaluation of anti-cancer activity

New Journal of Chemistry, 2018

Ag-Catalyzed synthesis of pyrrolopiperazine fused with oxazine/imidazole by the reaction of δ-alk... more Ag-Catalyzed synthesis of pyrrolopiperazine fused with oxazine/imidazole by the reaction of δ-alkynyl aldehydes and nucleophilic amines was performed. Several of these compounds were found to exhibit anti-cancer activity against cancer cell lines.

Research paper thumbnail of CCDC 1555220: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Research paper thumbnail of Computational Analysis of Epidermal Growth Factor Receptor Mutations Predicts Differential Drug Sensitivity Profiles toward Kinase Inhibitors

Journal of Thoracic Oncology, 2018

Introduction: A significant proportion of patients with lung cancer carry mutations in the EGFR k... more Introduction: A significant proportion of patients with lung cancer carry mutations in the EGFR kinase domain. The presence of a deletion mutation in exon 19 or L858R point mutation in the EGFR kinase domain has been shown to cause enhanced efficacy of inhibitor treatment in patients with NSCLC. Several less frequent (uncommon) mutations in the EGFR kinase domain with potential implications in treatment response have also been reported. The role of a limited number of uncommon mutations in drug sensitivity was experimentally verified. However, a huge number of these mutations remain uncharacterized for inhibitor sensitivity or resistance. Methods: A large-scale computational analysis of clinically reported 298 point mutants of EGFR kinase domain has been performed, and drug sensitivity profiles for each mutant toward seven kinase inhibitors has been determined by molecular docking. In addition, the relative inhibitor binding affinity toward each drug as compared with that of adenosine triphosphate was calculated for each mutant. Results: The inhibitor sensitivity profiles predicted in this study for a set of previously characterized mutants correlated well with the published clinical, experimental, and computational data. Both the single and compound mutations displayed differential inhibitor sensitivity toward firstand next-generation kinase inhibitors. Conclusions: The present study provides predicted drug sensitivity profiles for a large panel of uncommon EGFR mutations toward multiple inhibitors, which may help clinicians in deciding mutant-specific treatment strategies.

Research paper thumbnail of Consensus anticancer activity profiles derived from the meta-analysis of reference compounds for widely used cell lines

Future Medicinal Chemistry, 2018

Aim: To establish a standard reference for bioactivity of widely used anticancer compounds that m... more Aim: To establish a standard reference for bioactivity of widely used anticancer compounds that might be useful for meaningful interpretation of the cell viability data generated for novel synthetic derivatives. Materials & methods: Meta-analysis of published IC50 values was carried out for commonly used anticancer compounds and cell viability experiments were performed to validate the role of certain factors in drug activity. Results & conclusion: Variability in the published IC50 values was demonstrated. Based on median IC50 values derived from pooled published data, cell lines were classified as either sensitive or resistant. Further, factors that influence IC50 values were discussed, thus encouraging researchers to devise more rational experimental approaches to enhance the success rate in later stages of drug development.

Research paper thumbnail of Elucidation of conformational diversity of druggable enzymes and classification of chemical modulators based on inhibitor-bound structures

Journal of Biomolecular Structure and Dynamics, 2018

Proteins are remarkably flexible and exhibit multiple conformations each of which may be modulate... more Proteins are remarkably flexible and exhibit multiple conformations each of which may be modulated or stabilized by natural/synthetic ligands. Analysis of conformational diversity of an enzyme helps in understanding its function and has implications in biochemical and pharmacological applications. The variation observed among an array of structures of a particular enzyme can be indicative of its conformational diversity. In the present study, a large scale superposition analysis of enzyme-ligand co-crystal structures was performed revealing the presence of higher conformational diversity in the kinome A c c e p t e d M a n u s c r i p t than that of the non-kinome. In addition, a functional classification of chemical modulators (ligands) for each of the 149 druggable enzymes was performed based on the protein conformation they stabilized. The comprehensive functional classification of chemical modulators combined with the structural diversity profiling of druggable enzymes presented in this study may serve as a resource for chemical biology and drug development programs.

Research paper thumbnail of Computational analysis of ABL kinase mutations allows predicting drug sensitivity against selective kinase inhibitors

Tumor Biology, 2017

The ABL kinase inhibitor imatinib has been used as front-line therapy for Philadelphia-positive c... more The ABL kinase inhibitor imatinib has been used as front-line therapy for Philadelphia-positive chronic myeloid leukemia. However, a significant proportion of imatinib-treated patients relapse due to occurrence of mutations in the ABL kinase domain. Although inhibitor sensitivity for a set of mutations was reported, the role of less frequent ABL kinase mutations in drug sensitivity/resistance is not known. Moreover, recent reports indicate distinct resistance profiles for second-generation ABL inhibitors. We thus employed a computational approach to predict drug sensitivity of 234 point mutations that were reported in chronic myeloid leukemia patients. Initial validation analysis of our approach using a panel of previously studied frequent mutations indicated that the computational data generated in this study correlated well with the published experimental/clinical data. In addition, we present drug sensitivity profiles for remaining point mutations by computational docking analysi...

Research paper thumbnail of Silver-catalyzed synthesis of pyrrolopiperazine fused with oxazine/imidazole via a domino approach: evaluation of anti-cancer activity

New Journal of Chemistry, 2018

Ag-Catalyzed synthesis of pyrrolopiperazine fused with oxazine/imidazole by the reaction of δ-alk... more Ag-Catalyzed synthesis of pyrrolopiperazine fused with oxazine/imidazole by the reaction of δ-alkynyl aldehydes and nucleophilic amines was performed. Several of these compounds were found to exhibit anti-cancer activity against cancer cell lines.

Research paper thumbnail of Silver-catalyzed synthesis of pyrrolopiperazine fused with oxazine/imidazole via a domino approach: evaluation of anti-cancer activity

New Journal of Chemistry, 2018

Ag-Catalyzed synthesis of pyrrolopiperazine fused with oxazine/imidazole by the reaction of δ-alk... more Ag-Catalyzed synthesis of pyrrolopiperazine fused with oxazine/imidazole by the reaction of δ-alkynyl aldehydes and nucleophilic amines was performed. Several of these compounds were found to exhibit anti-cancer activity against cancer cell lines.