Table Of Content

GGeeoorrggiiaa SSttaattee UUnniivveerrssiittyy SScchhoollaarrWWoorrkkss @@ GGeeoorrggiiaa SSttaattee UUnniivveerrssiittyy Chemistry Dissertations Department of Chemistry 4-30-2008 AApppplliiccaattiioonn ooff CCoommppuutteerr--AAiiddeedd DDrruugg DDiissccoovveerryy MMeetthhooddoollooggiieess TToowwaarrddss tthhee RRaattiioonnaall DDeessiiggnn ooff DDrruuggss AAggaaiinnsstt IInnffeeccttiioouuss DDiisseeaasseess Prashanth Athri Follow this and additional works at: https://scholarworks.gsu.edu/chemistry_diss Part of the Chemistry Commons RReeccoommmmeennddeedd CCiittaattiioonn Athri, Prashanth, "Application of Computer-Aided Drug Discovery Methodologies Towards the Rational Design of Drugs Against Infectious Diseases." Dissertation, Georgia State University, 2008. doi: https://doi.org/10.57709/1059263 This Dissertation is brought to you for free and open access by the Department of Chemistry at ScholarWorks @ Georgia State University. It has been accepted for inclusion in Chemistry Dissertations by an authorized administrator of ScholarWorks @ Georgia State University. For more information, please contact [email protected]. APPLICATION OF COMPUTER-AIDED DRUG DISCOVERY METHODOLOGIES TOWARDS THE RATIONAL DESIGN OF DRUGS AGAINST INFECTIOUS DISEASES by PRASHANTH ATHRI Under the Direction of Dr. W. David Wilson ABSTRACT Computer-aided drug discovery involves the application of computer science and programming to solve chemical and biological problems. Specifically, the QSAR (Quantitative Structure Activity Relationships) methodology is used in drug development to provide a rational basis of drug synthesis, rather than a trial and error approach. Molecular dynamics (MD) studies focus on investigating the details of drug-target interactions to elucidate various biophysical characteristics of interest. Infectious diseases like Trypanosoma brucei rhodesiense (TBR) and P. falciparum (malaria) are responsible for millions of deaths annually around the globe. This necessitates an immediate need to design and develop new drugs that efficiently battle these diseases. As a part of the initiatives to improve drug efficacy QSAR studies accomplished the formulation of chemical hypothesis to assist development of drugs against TBR. Results show that CoMSIA 3D QSAR models, with a Pearson’s correlation coefficient of 0.95, predict a compound with meta nitrogens on the phenyl groups, in the combinatorial space based on a biphenyl-furan diamidine design template, to have higher activity against TBR relative to the existing compound set within the same space. Molecular dynamics study, conducted on a linear benzimidazole-biphenyl diamidine that has non-classical structural similarity to earlier known paradigms of minor groove binders, gave insights into the unique water mediated interactions between the DNA minor groove and this ligand. Earlier experiments suggested the interfacial water molecules near the terminal ends of the ligand to be responsible for the exceptionally high binding constant of the ligand. Results from MD studies show two other modes of binding. The first conformation has a single water molecule with a residency time of 6ns (average) that is closer to the central part of the ligand, which stabilizes the structure in addition to the terminal water. The second conformation that was detected had the ligand completely away from the floor of the minor groove, and hydrogen bonded to the sugar oxygens. INDEX WORDS: DNA minor groove binders, Trypanosoma brucei rhodesiense, 3D- QSAR, CoMSIA, Molecular Dynamics, Interfacial water, Water mediated Interactions. APPLICATION OF COMPUTER-AIDED DRUG DISCOVERY METHODOLOGIES TOWARDS THE RATIONAL DESIGN OF DRUGS AGAINST INFECTIOUS DISEASES by PRASHANTH ATHRI A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the College of Arts and Sciences Georgia State University 2008 Copyright by Prashanth Athri 2008 APPLICATION OF COMPUTER-AIDED DRUG DISCOVERY METHODOLOGIES TOWARDS THE RATIONAL DESIGN OF DRUGS AGAINST INFECTIOUS DISEASES by PPRASHANTH ATHRI Committee Chair: W. David Wilson Committee: Markus W. Germann David W. Boykin Electronic Version Approval: Office of Graduate Studies College of Arts and Sciences Georgia State University April 2008 DEDICATION My humble prostrations to the lotus feet of Amma iv ACKNOWLEDGEMENTS I believe it is impossible to list all the people who have helped through the past five years of my graduate life. Nevertheless, I think it is appropriate to begin with Dr. David Wilson who has been a great inspiration as well as a guide to me. I respect him not only as a great teacher but also as a very inspiring leader to his students. I found a lot of qualities in him that one should try to imbibe to become a good scientist as well as a nice human being. I think I speak for a lot of students in our lab when I say that we would be very lucky to work with advisors/managers who are as fair, understanding and reasonable as Dr. Wilson is through our careers. My parents, Mrs. D. Syamantakamani and Mr. C. R. Prabhakar, are the most important support structure in my life. They have given me all I have and continue to bless me with their love and affection. I am forever in gratitude to them. Dr. C. S. Prakash has always inspired me and has guided me since I set foot in the US. I have always respected his consul and consider him to be a true friend. I would like to thank him for all that he has done for me in the past few years. Shirsha is like a big brother to me and I cherish that relation constantly. I would like to thank Smt. Kumudvati (Kummi) for all her love and affection she gave me when I was growing up. I wish to thank a lot of friends who are always fun to be with, some old and some new: Venkatesha, Sulaiman Sheriff, Chandan Avalakki, Shivani Sharma, Laxmi Mukund, Vivek v Chandrashekariah, Kartik Tripathi, Shekar Nath, Jason Gilder and Leela Prakash. Research was a lot of excitement and fun with great co-workers, I do believe they have contributed a lot to my humble accomplishments; I want to thank Deacon Sweeney, Rupesh Nanjunda and Binh Nguyen. Finally, I wish to thank the Department of Chemistry, Georgia State University and our Chairman Dr. Baumstark for the continued support and encouragement through all these years. vi TABLE OF CONTENT DEDICATION.............................................................................................................................iv
 ACKNOWLEDGEMENTS.........................................................................................................v
 LIST OF TABLES........................................................................................................................x
 LIST OF FIGURES....................................................................................................................xii
 Chapter 1: Introduction...............................................................................................................1
 1.1 Introduction..............................................................................................................................1
 Chapter 2: 3D QSAR on a Library of Heterocyclic Diamidine Derivatives with Antiparasitic Activity..................................................................................................................24
 2.1 Introduction............................................................................................................................24
 2.1.1 Application of 3D QSAR to diamidines...........................................................................27
 2.2 Methods...................................................................................................................................29
 2.2.1 Dataset Selection..............................................................................................................29
 2.2.2 Determination of in vitro activity against Trypanosoma brucei rhodesiense (TBR).......30
 2.2.3 Molecular Modeling and Geometric Optimization..........................................................31
 vii

Description:
Computer-aided drug discovery involves the application of computer Models obtained from manual RMS alignment (as in 1 above) are referred to
ebook img

Application of Computer-Aided Drug Discovery Methodologies Towards the Rational Design of PDF

184 Pages·2017·3.62 MB·English
by  
Save to my drive
Quick download
Download
Upgrade Premium
Most books are stored in the elastic cloud where traffic is expensive. For this reason, we have a limit on daily download.

Preview Application of Computer-Aided Drug Discovery Methodologies Towards the Rational Design of

GGeeoorrggiiaa SSttaattee UUnniivveerrssiittyy SScchhoollaarrWWoorrkkss @@ GGeeoorrggiiaa SSttaattee UUnniivveerrssiittyy Chemistry Dissertations Department of Chemistry 4-30-2008 AApppplliiccaattiioonn ooff CCoommppuutteerr--AAiiddeedd DDrruugg DDiissccoovveerryy MMeetthhooddoollooggiieess TToowwaarrddss tthhee RRaattiioonnaall DDeessiiggnn ooff DDrruuggss AAggaaiinnsstt IInnffeeccttiioouuss DDiisseeaasseess Prashanth Athri Follow this and additional works at: https://scholarworks.gsu.edu/chemistry_diss Part of the Chemistry Commons RReeccoommmmeennddeedd CCiittaattiioonn Athri, Prashanth, "Application of Computer-Aided Drug Discovery Methodologies Towards the Rational Design of Drugs Against Infectious Diseases." Dissertation, Georgia State University, 2008. doi: https://doi.org/10.57709/1059263 This Dissertation is brought to you for free and open access by the Department of Chemistry at ScholarWorks @ Georgia State University. It has been accepted for inclusion in Chemistry Dissertations by an authorized administrator of ScholarWorks @ Georgia State University. For more information, please contact [email protected]. APPLICATION OF COMPUTER-AIDED DRUG DISCOVERY METHODOLOGIES TOWARDS THE RATIONAL DESIGN OF DRUGS AGAINST INFECTIOUS DISEASES by PRASHANTH ATHRI Under the Direction of Dr. W. David Wilson ABSTRACT Computer-aided drug discovery involves the application of computer science and programming to solve chemical and biological problems. Specifically, the QSAR (Quantitative Structure Activity Relationships) methodology is used in drug development to provide a rational basis of drug synthesis, rather than a trial and error approach. Molecular dynamics (MD) studies focus on investigating the details of drug-target interactions to elucidate various biophysical characteristics of interest. Infectious diseases like Trypanosoma brucei rhodesiense (TBR) and P. falciparum (malaria) are responsible for millions of deaths annually around the globe. This necessitates an immediate need to design and develop new drugs that efficiently battle these diseases. As a part of the initiatives to improve drug efficacy QSAR studies accomplished the formulation of chemical hypothesis to assist development of drugs against TBR. Results show that CoMSIA 3D QSAR models, with a Pearson’s correlation coefficient of 0.95, predict a compound with meta nitrogens on the phenyl groups, in the combinatorial space based on a biphenyl-furan diamidine design template, to have higher activity against TBR relative to the existing compound set within the same space. Molecular dynamics study, conducted on a linear benzimidazole-biphenyl diamidine that has non-classical structural similarity to earlier known paradigms of minor groove binders, gave insights into the unique water mediated interactions between the DNA minor groove and this ligand. Earlier experiments suggested the interfacial water molecules near the terminal ends of the ligand to be responsible for the exceptionally high binding constant of the ligand. Results from MD studies show two other modes of binding. The first conformation has a single water molecule with a residency time of 6ns (average) that is closer to the central part of the ligand, which stabilizes the structure in addition to the terminal water. The second conformation that was detected had the ligand completely away from the floor of the minor groove, and hydrogen bonded to the sugar oxygens. INDEX WORDS: DNA minor groove binders, Trypanosoma brucei rhodesiense, 3D- QSAR, CoMSIA, Molecular Dynamics, Interfacial water, Water mediated Interactions. APPLICATION OF COMPUTER-AIDED DRUG DISCOVERY METHODOLOGIES TOWARDS THE RATIONAL DESIGN OF DRUGS AGAINST INFECTIOUS DISEASES by PRASHANTH ATHRI A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the College of Arts and Sciences Georgia State University 2008 Copyright by Prashanth Athri 2008 APPLICATION OF COMPUTER-AIDED DRUG DISCOVERY METHODOLOGIES TOWARDS THE RATIONAL DESIGN OF DRUGS AGAINST INFECTIOUS DISEASES by PPRASHANTH ATHRI Committee Chair: W. David Wilson Committee: Markus W. Germann David W. Boykin Electronic Version Approval: Office of Graduate Studies College of Arts and Sciences Georgia State University April 2008 DEDICATION My humble prostrations to the lotus feet of Amma iv ACKNOWLEDGEMENTS I believe it is impossible to list all the people who have helped through the past five years of my graduate life. Nevertheless, I think it is appropriate to begin with Dr. David Wilson who has been a great inspiration as well as a guide to me. I respect him not only as a great teacher but also as a very inspiring leader to his students. I found a lot of qualities in him that one should try to imbibe to become a good scientist as well as a nice human being. I think I speak for a lot of students in our lab when I say that we would be very lucky to work with advisors/managers who are as fair, understanding and reasonable as Dr. Wilson is through our careers. My parents, Mrs. D. Syamantakamani and Mr. C. R. Prabhakar, are the most important support structure in my life. They have given me all I have and continue to bless me with their love and affection. I am forever in gratitude to them. Dr. C. S. Prakash has always inspired me and has guided me since I set foot in the US. I have always respected his consul and consider him to be a true friend. I would like to thank him for all that he has done for me in the past few years. Shirsha is like a big brother to me and I cherish that relation constantly. I would like to thank Smt. Kumudvati (Kummi) for all her love and affection she gave me when I was growing up. I wish to thank a lot of friends who are always fun to be with, some old and some new: Venkatesha, Sulaiman Sheriff, Chandan Avalakki, Shivani Sharma, Laxmi Mukund, Vivek v Chandrashekariah, Kartik Tripathi, Shekar Nath, Jason Gilder and Leela Prakash. Research was a lot of excitement and fun with great co-workers, I do believe they have contributed a lot to my humble accomplishments; I want to thank Deacon Sweeney, Rupesh Nanjunda and Binh Nguyen. Finally, I wish to thank the Department of Chemistry, Georgia State University and our Chairman Dr. Baumstark for the continued support and encouragement through all these years. vi TABLE OF CONTENT DEDICATION.............................................................................................................................iv
 ACKNOWLEDGEMENTS.........................................................................................................v
 LIST OF TABLES........................................................................................................................x
 LIST OF FIGURES....................................................................................................................xii
 Chapter 1: Introduction...............................................................................................................1
 1.1 Introduction..............................................................................................................................1
 Chapter 2: 3D QSAR on a Library of Heterocyclic Diamidine Derivatives with Antiparasitic Activity..................................................................................................................24
 2.1 Introduction............................................................................................................................24
 2.1.1 Application of 3D QSAR to diamidines...........................................................................27
 2.2 Methods...................................................................................................................................29
 2.2.1 Dataset Selection..............................................................................................................29
 2.2.2 Determination of in vitro activity against Trypanosoma brucei rhodesiense (TBR).......30
 2.2.3 Molecular Modeling and Geometric Optimization..........................................................31
 vii

Description:
Computer-aided drug discovery involves the application of computer Models obtained from manual RMS alignment (as in 1 above) are referred to
See more

The list of books you might like

Upgrade Premium
Most books are stored in the elastic cloud where traffic is expensive. For this reason, we have a limit on daily download.
DMCA & Copyright: Dear all, most of the website is community built, users are uploading hundred of books everyday, which makes really hard for us to identify copyrighted material, please contact us if you want any material removed.
Copyright @ PDFdrive.to, 2022 | We love our users