Workshop on Advances in Computer Aided Drug Design and Discovery Institute of Life Sciences, Ahmedabad University March 12-14, 2012

Transcription

1 Workshop on Advances in Computer Aided Drug Design and Discovery Institute of Life Sciences, Ahmedabad University March 12-14, 2012 A three days hands-on workshop on Advances in Computer Aided Drug Design and Discovery was organized by the Institute of Life Sciences (ILS), Ahmedabad University (AU), from March 12-14, This workshop, jointly organized with VLife Sciences, Pune, saw participation from both the pharma industry and academia. It included talks and discussions by some eminent speakers in the morning and a hands-on session post lunch on Computer Aided Drug design and Discovery and QSAR. During the inaugural function, Prof. Alok Dhawan, Director, ILS gave a genesis of the workshop and expressed the importance of in-silico approaches in drug design and discovery. He also expressed his appreciation and gratitude to Amrut Mody School of Management (AMSoM) and the Institute of Information and Communication Technology (IICT) for providing all the infrastructure support. Prof Bhavesh Patel, Director, AMSoM, while speaking on the occasion congratulated ILS on this venture. He further mentioned on how interdisciplinary education helps the society. Prof. A.H. Kalro, Provost, Ahmedabad University officially inaugurated the workshop using an in-silico approach and gave a brief account of the Ahmedabad University to the participants. He extended a cordial welcome to all and emphasized the need for generating trained human resource in this niche area and also congratulated ILS and the industry partner, VLife sciences for taking such an initiative in the pharma hub. Dr. Sami Mukhopadhyay, Principal Application Scientist, VLife Sciences, Pune, being the co-organizers of the workshop profoundly thanked AU and ILS for the infrastructure support provided for this workshop. 1

2 After the inauguration, Dr. Sami Mukhopadhyay spoke on the Basics of molecular modeling- Molecular mechanics, Optimization and Conformation Analysis. The fundamental concepts of some of the key initiation steps of any molecular modeling exercise were covered. These included basics of different methods of geometry optimization, force field or molecular mechanics, conformation generation and analysis and descriptors. Further, the basic approaches of any Computer Aided Drug Design (CADD) work in terms of Structure and Ligand Based Drug Design (SBDD and LBDD respectively) with details of each of these approaches were covered with an emphasis on utilizing both approaches in any CADD work to try to arrive at a meaningful consensus for realistic and practical solutions. This was followed by the lecture of Dr. M.T. Chhabria, L.M.College of Pharmacy who discussed the importance of CADD in New Drug Discovery. It was stated that new drug discovery is an intellectual, time consuming and expensive process. A typical drug discovery cycle, from lead to pharmacy shelf, can take about 14 years with the cost of ~ 800 million US dollars. In time, a new paradigm in drug discovery emerged, which includes early assessment of activity and selectivity of lead molecules, as well as their potential pharmacokinetics, ADME/Tox liabilities. This helps to reduce costly late-stage failures and reduce the time for successful development of new chemical entities (NCE s). CADD now plays vital role in the search for NCEs. Currently the main focus is on management of data sources and to improve design methodologies, computer programs to generate big libraries of compounds with desired pharmacological interest, development of new computational models to assess the potency and selectivity of lead candidates and to identify potential ADME/Tox liabilities. In the center of this paradigm shift is the application of computational techniques to ease the discovery of NCEs. Post lunch, a detailed hands-on session was carried out with participants on the fundamental initial steps of any molecular modeling work using VLifeMDS flagship suite of modeling program of VLife Sciences Technologies, India. The topics covered were drawing a molecule, energy minimization (optimization) of both small molecules/ligands as well as proteins, studying structure and bonding parameters of molecules, calculation of descriptors of molecules and generation and analysis of conformation of molecules. 2

3 The second day saw Dr. Kundan Ingale from VLife sciences converse on Homology modeling, protein analysis and Protein-ligand docking applications. The basic concepts of homology modeling, protein analysis and Protein-ligand docking applications as components of structure based drug design were covered with details of parameters to consider for validating the homology model structure of protein. The strengths and weakness of protein-ligand docking were covered with details of scoring functions. Next, Dr. Sairam Kalapatapu, Zydus Research Centre spoke on Rational Drug Design, how rational is it? Attention was drawn to the fact that computer aided drug design is not a panacea for problems in drug discovery. It has to be complemented with experimental evidence that perceived hypothesis stands to the results of the day. Also important is to be prepared for surprises (serendipitous drug discovery cases were discussed). Structure based drug design, phamacophore generation and screening was also discussed. Emphasis was given to fragment based drug design and docking with suitable examples captured from literature. Emerging topics in computer-aided drug design such as polypharmacology, systems biology were discussed with suitable examples. Molecular dynamics simulations were discussed in detail with subtler details of intermolecular hydrogen bonding interactions and relay like fashion of making and breaking of hydrogen bonds in ligand SC-558 exit from cyclooxygenase-2. The hands-on session focused on the different aspects of protein modeling and Structure Based Drug Design. This included performing protein preparation steps, performing BLAST, homology modeling, protein model validation checks, studying Ramachandran plots, protein analysis in terms of active sites/channels analysis, protein-ligand docking involving judicious use of dock scoring functions and proteinligand binding interaction studies. The last day of the workshop began with a lecture on QSAR and Molecular Modeling Studies on Antihistamines (H 1 ) by Dr. A. K. Saxena, CSIR- Central Drug Research Institute, Lucknow. The talk revolved around the fact that histamine controls a multitude of physiological functions by activating specific receptors on target cells. It exerts its effects by binding to four different histamine receptors (H 1-3

4 H 4 ), which all belong to the large family of G protein-coupled receptors (GPCR). Research and development of H 1 ligand has focused on antagonists which are used for their anti-allergy effects in the periphery. Recent understanding of the clinical importance of H 1 receptors in brain, however, suggests the pharmacotherapeutic potential of H 1 agonists in neurodegenerative and neuropsychiatric disorders. Despite the therapeutic importance of the H 1 receptor for many years the molecular features of the H 1 receptor protein had been unknown except some efforts in the recent past. In view of it and in continuation of our work on 3D-pharmacophore on antihistamine H 1 and homology model of histamine H 1 receptor, molecular modeling studies on some novel pyrazinopyridoindole class of antihistamine H 1 have been carried out to validate the models and to explain the behavior of earlier identified outliers. Prof. Alok Dhawan, ILS discussed the role of In-silico approaches in mechanistic toxicology. The need for use of different commercial softwares (1) Knowledge based and (2) Correlation based available for undertaking in-silico toxicology studies was discussed. The want for using a multipronged approach to unravel the genotoxicity of benzene was demonstrated using softwares to formulate a hypothesis and then work around it using in-silico as well as wet lab approaches. QSAR was used to assess the impact of various benzene metabolites on the inhibition of the ATP domain of human topoisomerase IIα enzyme. Further to validate the results the enzyme was purified and inhibition of ATPase activity was measured in the presence of benzene and its metabolites. Both in-silico and wet lab experiments showed that the quinine metabolites of benzene are responsible for the inhibition of ATP domain of human topoisomerase IIα enzyme leading to DNA damage and ultimately cancer. The lab session for the day focused on different aspects of Ligand Based Drug Design. The emphasis was 2D and 3D QSAR with details of descriptor calculation, training and test set selection, variable selection, QSAR model building, QSAR model analysis and validation checks, parameters to use for best model selection and subsequent use of it for activity prediction and lead optimization. In that light, the strengths and weaknesses of 2D and 3D QSAR were highlighted together with explanation of the need for alternative fragment based QSAR methods like VLifeGQSAR as a solution to tackling complex QSAR issues of prediction accuracy and lead optimization. 4

5 Moving towards the valedictory, Prof. Dhawan and Dr. Mukhopadhyay together gave away the certificates to the participants and took this opportunity to once again express their appreciation to the participants for their inquisitiveness and curiosity. Prof. Dhawan also articulated his positive reception towards the organizing team, AU-IICT and AMSoM for all assistance rendered. 5

6 Participants and faculty of CADD Workshop 6