Histone Acetyltransferase Inhibitors, From Screening to Optimization – A Tricky Track
Conference Talk by Dr Baell
Talk Abstract: There is currently great interest in compounds that modulate epigenetics. With respect to some epigenetic targets, such as histone decacetylases (HDACs), many inhibitors have been successfully developed and are in clinical trials for a variety of indications. Similarly, bromodomains have been shown, somewhat unexpectedly by some, to be highly druggable. However, there is an elephant in the room, and that is the histone acetyltransferase (HAT) family, which is large but essentially “undrugged” and barely has any compounds that could be considered to be useful tools. Why is it so hard to find good tool compounds for these enzymes?
Not so long ago we undertook HTS against a MYST HAT and eventually discovered a genuine hit that we have recently just optimized to nanomolar levels of inhibition. However, we encountered many problems en route. In this talk we will discuss such issues and how these could help explain why there are so few, if any, useful tool compounds for these enzymes.
Grab the chance to get in touch with Dr Jonathan Baell, from Monash University, Australia at SELECTBIO“MedChem 2017” meeting on 14- 15 September, 2017 at Hotel Le Meridien, Bengaluru.
Freezing Essential Enzyme Motion for Catalysis: An Efficient Approach for Shikimate Kinase Inhibition
Conference Talk by Dr. Conception
Talk Abstract: Most of the approaches used in the structure-based design of inhibitors of enzymes are based on docking or virtual screening studies using the available crystal structures in which the enzyme is considered a rigid mold. However, enzymes are “dynamic” systems that are able to adopt diverse conformations during catalysis and this could also be exploited in inhibitor design since the flexibility is essential for catalysis. It seems reasonable that for enzyme inhibitor design, in addition to stabilizing a closed disposition of the active site that prevents the entry of the substrate(s), disabling the closure of the active site for catalysis could also be an interesting alternative strategy. This motion-based approach allows the design of ligands that target additional cavities generated during this motion but have limited (or no) access in the closed conformation.
The possible development of new antibiotics by the selective and effective inhibition of shikimate kinase (SK), which is an essential enzyme in bacteria that does not have any counterpart in human cells, is presented. Competitive reversible inhibitors of the SK enzyme from M. tuberculosis and H. pylori that block the closure of the active site by reducing the flexibility of the LID and SB domains were identified showing to have good in vitro activity.
Revival, Renewal and Renaissance in Ayurvedic Therapeutics as Paths to Natural Drugs
Conference Talk by Dr. Vaidya
Talk Abstract: Asian Health Systems offer a huge potential for the discovery of natural drugs. Ayurveda, used by more than 80% of Indians, needs ‘a bedside to bench’ R&D approach. Widely used therapies for common diseases can be revived systematically by Ayurvedic Pharmacoepidemiology (AyPE) and Observational Therapeutics (OT). Remedies and modalities currently not in common practice but described in classical texts/clinical notes, need to be renewed by the approach of a documented reversal of Ayurvedic pathogenesis, with validated clinical/laboratory markers and designs of n=1 studies and sequential trials.
Drugs in practice may be repurposed as convenient/novel dosage forms for new indications. A renaissance in therapeutics can be ushered in by trans-disciplines of Reverse Pharmacology (RP) and Translational Research (TR). There is an urgent need to train more Vaidya-Scientists, to create Centres of Excellence in AyPE, OT, RP, TR and to provide adequate infrastructure with resources. The hints, hits, leads and candidates from Ayurveda therapeutics do exist as naturals for cancer, diabetes, arthritis, neurodegenerative disorders and hepatitis.
Dr. Vaidya is from a lineage of Ayurveda and medicine; the heritage archives are a treasure trove for new leads from natural products. He evolved Reverse Pharmacology (RP) to explore this heritage. Dr. Vaidya has more than 290 research publications to his credit. He has guided graduate students in basic and clinical drug research and Ayurveda.
The Determinants of Therapeutic Outcomes in Ayurveda: Challenges to Drug Discovery
Conference Talk by Dr. Raut
Talk Abstract: Ayurveda is a clinically oriented healthcare system founded on nature-sensitive fundamental doctrines. Profundity of this clinical science is evident in its approach of considering every possible matter as a potential therapeutic substance. Integral therapeutic management in Ayurveda involves choice of diet, exercise, lifestyle, special procedures and drugs. The therapeutic outcome to the integral management is a conjoint response determined by the ‘Activity-Property Matrix’ of remedies used, effects of the non-drug measures and patient factors. Research in Ayurveda therapeutics demand a robust documentation of clinical observations, shared professional experiences, classical literature cue and Ayurvedic rationale to determine the productive outcome.
‘Observational Therapeutics’ and ‘Ayurvedic Pharmaco-epidemiology’ which attempt to address the experiences of clinical and community practices may provide hints and hits for the therapeutic choices in identified clinical conditions. However, making informed-intuitive choice from empirical-experiential noise is extremely crucial. A consensual validity of experts should guide the choices and outcome-determining variables of the drug response. This would guide further ‘Reverse pharmacology’ to rationally explore and translate these therapeutic experiences for novel clinical applications and new drug discovery, by appropriate and relevant experimental and clinical designs.
Dr. Raut proposes specific response determinants which would enhance the value of the R&D studies in Ayurveda and ensure translational outcomes as new drugs. These determinants can be broadly categorized into ‘product-specific’ and ‘patient-specific’ groups. Product-specific may be illustrated as Ayurvedic kalpa (classical form), Aushadhi prayoga (dosage regimen), Aushadhi kala (dosage regimen), Anupana (vehicle for administration), Ahara – Vihara (diet and life-style regimen) etc. Patient-specific factors are Rugna Prakriti (patient’s constitution), Shat–kriyakala (stage of a disease), Samutthana–Vishesha (causative factors), Dosh–Dushya–Adhishthan (pathological factors), Vyadhi Lakshana (clinical features) etc. Nevertheless, standardization and rationalization of traditional Ayurvedic products are also mandatory and integration of principles of Ayurvedic Pharmaceutics is equally essential for the healthcare of a large population.
Dr. Ashwinikumar Raut is Director, Clinical Research & Integrative Medicine at Kasturba Health Society’s Medical Research Centre, Mumbai. Dr. Raut is an Ayurveda consultant and Investigator from Mumbai. He is faculty and consultant to premier medical institutes and hospitals in Mumbai. He also gives consultation to Ayurveda industry.
Assay Miniaturization Strategies: Smaller and Cheaper Cell-Based Assays for HCA
Learn from Dr Anthony Davies, Director, TCIQ, Queensland, Australia at CellTech India 2015 in Bangalore on March 2-3, 2015.
To sustain the viability of large-scale research programs running in academia and industry (especially when considering the current global economic climate), it is essential to reduce research costs wherever possible. With the advent of micron resolution robotics and nano-litre capable liquid handlers, assay miniaturization for large-scale High-Content Screening is now possible. The advantages of miniaturization are clear, when one considers the savings in reagents and experimental materials and experimental turnaround times. However miniaturization can also be costly to set up and difficult to deploy.
High Content Screening and analysis (HCS/A) technologies have over the last 15 years become widely adopted in both the academic and industrial research sectors. The acceptance of these technologies has in the large part been due to their demonstrable utility as both drug-discovery and basic research tools, indeed these imaging technologies such as HCS/A have the capability of providing researchers with a ready means of performing both large scale primary screens as well as permitting more detailed downstream analysis. Alongside the rapid uptake of these technologies, we have also seen a concomitant increase in the demand for more refined and flexible hardware and biologically relevant cell based assay approaches that can be utilized for translational research. Currently one of the biggest drivers in the field is the need to improve the physiological relevance of cell based assays used within translational research campaigns. To achieve these aims many are turning their attention to the use of primary cells and/or 3 dimensional cellular assay models. In summary this presentation will cover the key technological and methodological approaches we are currently implementing within our High Content Analysis workflows to meet our translational research goals. This talk will be presented at CellTech India 2015 in Bangalore on March 2, 2015 by Dr. Anthony Mitchell Davies, Queensland, Australia. Dr. Anthony Mitchell Davies is currently the Center Director: Translational Cell Imaging, Institute of Health Biomedical Innovation, Australia