Drug Discovery Podcasts

Introduction: IonCure’s Vision for Epilepsy, Depression and SARS-CoV2-Related Drug Discovery

Adesh Vaidya and Sukant Khurana discuss how for three missions, epilepsy, depression, and SARS-CoV2 related drug discovery, IonCure is committed to reinvesting all the revenues and encourages citizen science.

E01: Challenges in Drug Discovery

Why is drug discovery time consuming? What limits the conversion of scientific publications to medicines or drugs?

There are three main reasons as we see –

1. Lack of systematic categorization of bio-medical information in a usable format,
2. Thinking of cell signaling as linear pathways rather than in terms of nodes and networks of interacting proteins
3. Insufficient information on the nodes that need to be targeted for efficient outcomes.

E02: Steps from Pharmacology to Drug Consumption

New molecules are identified to kill cancer cells or hailed as miracle treatments. Why do these reported molecules take a seemingly inordinate time to reach patients?

1. When a research paper claims that a chemical kills cancer cells, this is plain pharmacology. It tells you the concentration of the chemical that kills a certain percentage of the chosen cell type in a specified time period. This kind of a study narrows down from ‘n’ compounds to 1-2, based on their cytotoxicity. The relevance of the cell type or cell line used, inclusion of appropriate controls and experimental conditions become important parameters.
2. The relevance of the identified compounds to an actual cancer is not revealed by the pharmacology. The other things that need to be considered are toxicity of the compound to non-cancerous cells, pharmacokinetics (absorption, distribution, metabolism, exertion) of the compound and the pharmacodynamics which is the effect of the drug on the body. Of relevance to pharmacodynamics is the specificity of the drug to the disease mechanism or protein of interest, and non-specific interactions leading to side effects.
3. Differences in physiology and metabolism between small mammals and humans can also delay rug introduction
4. In silico efforts can reduce the time and cost of these initiatives

E03: Where do Most Drug Candidates Fail?

More than 50% drug candidates fail in Pharmacokinetics (ADME) and animal toxicity. Old school drug discovery – a lot of effort went into initial screening, testing and development. Suffered from late stage setbacks due to ADEM and toxicity Big pharma tend to purchase drugs post-development, rather than innovation in their pipelines. Some pharma companies are using AI to reduce failure. Combination of AI with biological knowledge, and the ability to use these repeatedly and reproducibly to develop drugs is the key to success.

E04: Conventional Drug Discovery

What are the major steps in conventional drug discovery?

There are three major steps –

1. Target identification and validation. Determine which protein or pathway should be targeted, validate the choice of target, define the chemical space for profiling of drugs. Start with millions of compounds and end up with ~100 – 300 leads.
2. Test lead specificity. In silico docking of lead compounds to the desired target and to other cellular proteins. Followed by chemical modifications to the pharmacophore to improve efficacy or specificity or both. Narrows the compounds to ~30
3. PK, PD, Toxicity. In silico testing and animal studies. Can be improved through chemical diversification, or results in 3-10 hits that are taken up for pre-clinical and clinical studies. A lot of PK, PD and toxicity can be predicted in silico, but there is not alternative to animal studies and human safety.

E05: Drug Repurposing

De novo drug development cycles are long taking 15-22 years, lots of money and effort. Repurposing starts with chemicals that are certified by regulatory bodies such as the FDA, and are already being consumed as drugs, and their pharmacokinetics are known. Repurposing asks – Can any of these compounds be used to treat other medical functions. Some of the success stories of repurposing include Viagra, that targets eNOS was developed to treat angina, is now used in combating erectile dysfunction.

The widely prescribed diabetes drug metformin has found uses in PCOD, cardiovascular problems and cancers, and Triclosan from mouthwash and toothpaste can be used against drug-resistant malarial parasites. In fact Triclosan’s application to malaria was uncovered using AI in 2 months.

Drug repurposing can save a lot of time and money.

E06: Plants as a Starting Point for Drug Discovery

A common perception is that modern pharmaceuticals are the products of human chemistry. However, some of the most common drugs, originate from plants. Three striking examples are discussed here –

Metformin – from French lilac.

Cardiotonics – from Digitalis

Salicyclic acid – Spirea sp

Therefore, it is not wrong to think of phytochemicals and plants as starting material for targeted molecular therapeutics. Multiple traditional systems of medicine rely on plants, which can be useful sources of therapeutics. Surveys among indigenous populations or tribes to learn about such remedies can be very useful in providing new solutions. It becomes important to identify the active ingredient and taking it further for testing and development into drugs.

We are a Drug discovery, drug development and manufacturing company that puts services ahead of profits.

E07: Supplements from Plants

How do you know that phyto-supplements work?

What is the mechanism of action?

There are concerns about the source of the plant material, appropriate quality controls, the harvest season.

All of this and other factors can influence the content of the active chemical ingredient in the supplement.

Often, many phytochemicals may not directly contribute to activity, but provide synergism with the active component.

The continuum between food, supplement and medicines, means that you have to be careful about allergic and toxic reactions.

Plant extracts like bitter gourd affect cell biology at multiple levels, helping in the control of diabetes.

Ioncure has some leads that affect epigenetics and could be tested as diabetes therapeutics.

Appropriate environmental and biotic stresses lead to the production of secondary metabolites that could be active phytochemicals.

E08: What Makes a Good Supplement?

What gives supplements a bad name?

1. Lack of QC in terms of stringency in sourcing, active component content
2. Toxicology or lack thereof.
3. Consumers going on a pill-popping spree

How can we improve supplements?

1. Better safety standards through in a panel of in silico, animals and human organoids.
2. Inclusion of hyper-local food with interesting nutritional / metabolic activities.
3. An appropriate combination of traditional knowledge and modern science to ensure appropriate processing of plant sources to get the appropriate activity.

How can supplements enhance human longevity?

1. Create a database of all medicinal plants and their various activities – huge focus at IonCure
2. Ageing involves multiple things in the body – research seems to focus on very few of these.
3. Supplements remove poorly performing cells, epigenetic changes, maintaining stem cells, enhancing apoptosis, energetics and oxidative stress.

More regulation, more consumer awareness about preventing cross-medication, safety and efficacy of the supplement, use of neutral adjuvants. One of the fertile areas in the use of supplements is the ability to target multiple points can be sued to improve the duration of a healthier life span.

E09: Supplements to Increase Longevity

First, what are the factors that go awry during aging? Biologically some of the important factors are genetic material organization, loss of DNA and genomic stability, DNA methylation, intracellular signaling – coupled to caloric restriction and electron transport chain, intermittent fasting, differentiation-dedifferentiation of stem cells, Islets of Langerhans and neurons, Reactive oxygen species, Triggering autophagy, proteostasis and rectifying protein mistrafficking, hormonal changes. Each of these provides mechanistic targets for supplement development.

Second, how does Ioncure approach anti-aging? IonCure has more than 40 single-molecule leads on targeting the ETC to recreate a younger cellular state. We have supplements that modify inflammation and immune function, and our global surveys have revealed novel phytoleads. There are ways of targeting fibrosis. We may also have stem cell and epigenetic leads. There are also leads to targeting neurodegeneration.

Third, the path from computational solutions to translational research at IonCure. We have funding from the Govt of India, and hope to bootstrap fund raising.

E10: Drug Targets

How does a potential drug discoverer pick a target to study? Does the pathogen or cancerous tissue make for a better target? Or should the discoverer focus on the affected cell’s receptors, enzymes, ion channels or other pathways? Sukant Khurana discusses these thorny dilemmas with Dr. Mahua Ghosh.

E11: Picking a Disease

Picking a disease for drug discovery is a complex choice based on prevalence, cost of drug manufacture and delivery and ultimately profitability for the investor/manufacturer. Sukant Khurana discusses the motivations and imperatives in diseases choice with Dr. Mahua Ghosh.

E12: Rare Diseases

Discovering drugs for rare diseases can be financially unrewarding for major pharma companies, and becomes the default responsibility of taxpayer-funded science. Sukant Khurana discusses the challenges in drug discovery for rare diseases with Dr. Mahua Ghosh.

E13: Key Challenges in HERG Channel Toxicology

HERG channel liability is a major toxicology channel a drug must cross. Sukant Khurana discusses the key challenges in HERG channel toxicology with Dr. Saba Munnawar, who has experience in patch-clamp recording, computational drug discovery, and HERG channels.

E14: Nanoinformatics for Drug Delivery

Nanotechnology and its specific branch nanobiology are ushering in a revolution in the biomedical field. Applying data science approaches to it and conducting nanoinformatics has immense potential. Dr. Animikh Ray tells Sukant Khurana about application of nanoinformatics for drug delivery.

E15: Metabolic Engineering for Designing Better Phyto-Pharmaceuticals

To have most effective plant extract (phyto-extract) for any disease, the plant must be rich in active phytochemical. In addition to selection, callus culture, and breeding approaches, there is the modern approach of metabolic engineering. We discuss with Mr. Avinash Kumar, who has worked extensively on caffeine metabolism and antioxidant response to SARS-CoV2, about the scope of metabolic engineering for designing better phyto-pharmaceuticals.

E16: Why One Needs Formulations

Formulations are everywhere, in paint, toothpaste and in medicines you take. We discuss why one needs formulations. Dr. Animikh Ray, an expert in nanoinformatics and formulations, sheds light on this topic.

E17: Challenges in Taking Discoveries from Bench to Bedside

We discuss why despite advances in formulations research, there is gulf in academic research and applications. Dr. Animikh Ray discusses with Dr. Sukant Khurana the challenges in taking discoveries from bench to bedside.

E18: Autodock 4.2, Autodock Vina in Docking Studies

Molecular docking is an essential tool in drug discovery. It shows how a molecule can bind to a ligand. Dr. Amit Kumar Shrivastava, a member of Ioncure hailing from Kathmandu, discusses broadly the use of Autodock 4.2, Autodock Vina in docking studies with Sukant Khurana.

E19: Docking and Molecular Dynamic Simulations and Experimental Studies

Dr. Zahra Ali Kamaz, who is a researcher at University of Karbala, Iraq, has been collaborating with Ioncure on two projects. She works on microflora and antibiotic resistance issues, and SARS-CoV2. Dr. Khurana and Dr. Kamaz discuss how phytochemicals can be studied through docking and molecular dynamic simulations and then experimental studies to bind to receptors which are responsible for update of viruses, such as SARS-CoV2.

E20: Challenges for Drug Discovery in Academia and Industry

Dr. Brooks Robinson and Dr. Sukant Khurana discuss why academia is broken for drug discovery and in general meeting requirements of society.

E21: Why Resilience is Vital

Dr. Brooks Robinson, a program director at the National Institute of Human Resilience at Colorado Springs discusses why resilience is vital during the times of Covid-19. He also touches on why response of individuals to traumatic events can be very different.