Agastya Prakash Bhati

Agastya Prakash Bhati
University College London | UCL · Department of Chemistry

PhD

About

41
Publications
2,307
Reads
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441
Citations
Introduction
I am currently pursuing PhD at the Department of Chemistry of University College London, UK. I am working on developing a methodology to theoretically calculate reproducible and precise drug-protein binding free energy using molecular dynamics simuations. I completed BS-MS dual degree course from Indian Institute of Science Eduation and Research (IISER) Mohali, India, in May 2014. My MS research project was under Prof. N. Sathyamurthy, IISER Mohali in the field of Theoretical Chemistry.
Additional affiliations
September 2015 - present
University College London
Position
  • Postgraduate Teaching Assistant
Description
  • Working as a teaching assistant for several basic and advanced level Chemistry undergraduate/postgraduate courses.
January 2014 - April 2014
Indian Institute of Science Education & Research Mohali
Position
  • Research Assistant
Description
  • Teaching assistant for the semester long undergraduate laboratory course on Quantitative Chemical Analysis.
August 2013 - August 2014
Indian Institute of Science Education & Research Mohali
Position
  • Pattern of concentric circles in Passiflora Incarnata: an activator-inhibitor model
Description
  • Turing’s Reaction-Diffusion (RD) model was employed to understand the formation of the pattern of concentric circles, similar to that of Passiflora Incarnata.
Education
August 2009 - May 2014

Publications

Publications (41)
Article
Full-text available
Computational methods and recently modern machine learning methods have played a key role in structure-based drug design. Though several benchmarking datasets are available for machine learning applications in virtual screening, accurate prediction of binding affinity for a protein-ligand complex remains a major challenge. New datasets that allow f...
Preprint
Despite the increasingly wide availability of computational resources, it is still challenging for researchers to perform comprehensive molecular dynamics (MD) simulations on an industrial scale. With ensemble approaches, great accuracy and precision are achievable at the cost of considerable computational efforts. There is a trade-off between accu...
Article
Full-text available
Optimization of binding affinities for compounds to their target protein is a primary objective in drug discovery. Herein we report on a collaborative study that evaluates a set of compounds binding to ROS1 kinase. We use ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration wit...
Article
Full-text available
The binding free energy between a ligand and its target protein is an essential quantity to know at all stages of the drug discovery pipeline. Assessing this value computationally can offer insight into where efforts should be focused in the pursuit of effective therapeutics to treat a myriad of diseases. In this work, we examine the computation of...
Article
Full-text available
Optimization of binding affinities for ligands to their target protein is a primary objective in rational drug discovery. Herein, we report on a collaborative study that evaluates various compounds designed to bind to the SET and MYND domain-containing protein 3 (SMYD3). SMYD3 is a histone methyltransferase and plays an important role in transcript...
Preprint
Optimization of binding affinities for ligands to their target protein is a primary objective in rational drug discovery. Herein we report on a collaborative study that evaluates various compounds designed to bind to the SET and MYND domain-containing protein 3 (SMYD3). SMYD3 is a histone methyltransferase and plays an important role in transcripti...
Article
Full-text available
The accurate and reliable prediction of protein-ligand binding affinities can play a central role in the drug discovery process as well as in personalized medicine. Of considerable importance during lead optimization are the alchemical free energy methods that furnish an estimation of relative binding free energies (RBFE) of similar molecules. Rece...
Preprint
Optimization of binding affinities for compounds to their target protein is a primary objective in drug discovery. Herein we report on a collaborative study that evaluates a set of compounds binding to ROS1 kinase. We use ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration wit...
Preprint
Optimization of binding affinities for compounds to their target protein is a primary objective in drug discovery. Herein we report on a collaborative study that evaluates a set of compounds binding to ROS1 kinase. We use ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration wit...
Preprint
The accurate and reliable prediction of protein-ligand binding affinities can play a central role in the drug discovery process as well as in personalised medicine. Of considerable importance during lead optimisation are the alchemical free energy methods that furnish estimation of relative binding free energies (RBFE) of similar molecules. Recent...
Preprint
Full-text available
The binding free energy between a ligand and its target protein is an essential quantity to know at all stages of the drug discovery pipeline. Assessing this value computationally can offer insight into where efforts should be focused in the pursuit of effective therapeutics to treat myriad diseases. In this work we examine the computation of alche...
Preprint
Full-text available
The accurate and reliable prediction of protein-ligand binding affinities can play a central role in the drug discovery process as well as in personalised medicine. Of considerable importance during lead optimisation are the alchemical free energy methods that furnish estimation of relative binding free energies (RBFE) of similar molecules. Recent...
Article
Full-text available
The race to meet the challenges of the global pandemic has served as a reminder that the existing drug discovery process is expensive, inefficient and slow. There is a major bottleneck screening the vast number of potential small molecules to shortlist lead compounds for antiviral drug development. New opportunities to accelerate drug discovery lie...
Article
Full-text available
Although researchers have been working tirelessly since the COVID-19 outbreak, so far only three drugs – remdesivir, ronapreve and molnupiravir – have been approved for use in some countries which directly target the SARS-CoV-2 virus. Given the slow pace and substantial costs of new drug discovery and development, together with the urgency of the m...
Article
Full-text available
Based on a careful examination of the onset of violet colored dots along the filaments in the developing floral bud stage and the formation of alternating bands of violet and white color in the matured flowers of Passiflora incarnata (Passion flower), it is concluded that the pattern arises from a competition between the production of violet colore...
Preprint
Full-text available
Although researchers have been working tirelessly since the COVID-19 outbreak, so far only two drugs – remdesivir and ronapreve – have been approved for use in some countries which directly target the SARS-CoV-2 virus. Given the slow pace and substantial costs of new drug discovery and development, together with the urgency of the matter, repurposi...
Preprint
Although researchers have been working tirelessly since the COVID-19 outbreak, so far only two drugs – remdesivir and ronapreve – have been approved for use in some countries which directly target the SARS-CoV-2 virus. Given the slow pace and substantial costs of new drug discovery and development, together with the urgency of the matter, repurposi...
Preprint
Full-text available
Although researchers have been working tirelessly since the COVID-19 outbreak, there is yet no effective drug found to directly treat the disease. Given the slow pace and substantial costs of new drug discovery and development, repurposing of existing drugs for the ongoing disease becomes an attractive proposition. In a recent study, a high-through...
Preprint
Although researchers have been working tirelessly since the COVID-19 outbreak, there is yet no effective drug found to directly treat the disease. Given the slow pace and substantial costs of new drug discovery and development, repurposing of existing drugs for the ongoing disease becomes an attractive proposition. In a recent study, a high-through...
Article
Full-text available
COVID-19 has claimed more than 2.7 × 106 lives and resulted in over 124 × 106 infections. There is an urgent need to identify drugs that can inhibit SARS-CoV-2. We discuss innovations in computational infrastructure and methods that are accelerating and advancing drug design. Specifically, we describe several methods that integrate artificial intel...
Preprint
Full-text available
The race to meet the challenges of the global pandemic has served as a reminder that the existing drug discovery process is expensive, inefficient and slow. There is a major bottleneck screening the vast number of potential small molecules to shortlist lead compounds for antiviral drug development. New opportunities to accelerate drug discovery lie...
Article
Full-text available
The TIES (Thermodynamic Integration with Enhanced Sampling) protocol is a formally exact alchemical approach in computational chemistry to the calculation of relative binding free energies. The validity of TIES relies on the correctness of matching atoms across compared pairs of ligands, laying the foundation for the transformation along an alchemi...
Article
Full-text available
A central quantity of interest in molecular biology and medicine is the free energy of binding of a molecule to a target biomacromolecule. Until recently, the accurate prediction of binding affinity had been widely regarded as out of reach of theoretical methods owing to the lack of reproducibility of the available methods, not to mention their com...
Article
A central quantity of interest in molecular biology and medicine is the free energy of binding of a molecule to a target biomacromolecule. Until recently, the accurate prediction of binding affinity had been widely regarded as out of reach of theoretical methods owing to the lack of reproducibility of the available methods, not to mention their com...
Preprint
Full-text available
COVID-19 has claimed more 1 million lives and resulted in over 40 million infections. There is an urgent need to identify drugs that can inhibit SARS-CoV-2. In response, the DOE recently established the Medical Therapeutics project as part of the National Virtual Biotechnology Laboratory, and tasked it with creating the computational infrastructure...
Preprint
Full-text available
The drug discovery process currently employed in the pharmaceutical industry typically requires about 10 years and $2-3 billion to deliver one new drug. This is both too expensive and too slow, especially in emergencies like the COVID-19 pandemic. In silicomethodologies need to be improved to better select lead compounds that can proceed to later s...
Article
Full-text available
The accurate prediction of the binding affinity changes of drugs caused by protein mutations is a major goal in clinical personalised medicine. We have developed an ensemble-based free energy approach called thermodynamic integration with enhanced sampling (TIES), which yields accurate, precise and reproducible binding affinities. TIES has been sho...
Conference Paper
Full-text available
The accurate prediction of the binding affinities of ligands to proteins is a major goal in drug discovery and personalised medicine. The use of in silico methods to predict binding affinities has been largely confined to academic research until recently, primarily due to the lack of their reproducibility, as well as unaffordably longer time to sol...
Article
Full-text available
The alchemical free energy methods have gained much importance recently from several reports of improved ligand-protein binding affinity predictions based on their implementation using molecular dynamics simulation. A large number of variants of such methods implementing different accelerated sampling techniques and free energy estimators are avail...
Article
Optimisation of ligand binding affinity to the target protein of interest is a primary objective in small-molecule drug discovery. Until now, the prediction of binding affinities by computational methods has not been widely applied in the drug discovery process, mainly due to its lack of accuracy and reproducibility, as well as the long turnaround...
Article
An understanding of the determinants of the thermal stability of thermostable proteins is expected to enable design of enzymes that can be employed in industrial biocatalytic processes carried out at high temperatures. A major factor that has been proposed to stabilize thermostable proteins is the high occurrence of salt bridges. The current study...
Article
Binding free energies of bromodomain inhibitors are calculated with recently formulated approaches, namely ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration with enhanced sampling). A set of compounds is provided by GlaxoSmithKline, which represents a range of chemical funct...
Article
Full-text available
The accurate prediction of the binding affinities of ligands to proteins is a major goal in drug discovery and personalised medicine. The time taken to make such predictions is of similar importance to their accuracy, precision and reliability. In the last few years, an ensemble based molecular dynamics approach has been proposed that provides a ro...
Article
Full-text available
We present FabSim, a toolkit developed to simplify a range of computational tasks for researchers in diverse disciplines. FabSim is flexible, adaptable, and allows users to perform a wide range of tasks with ease. It also provides a systematic way to automate the use of resourcess, including HPC and distributed resources, and to make tasks easier t...

Questions

Question (1)
Question
I checked the manual (2010 version) but could not find any information on TDDFT there. The version 2012 of manual has the keyword "tddft", but it does not accept. I am using MOLDEN 2010. I have also attached my input file (in txt format).

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Project (1)
Project
Accurate theoretical prediction of free energy change associated with the binding of drug molecule with target protein from their free states, also known as binding affinity, is central to the fields of personalised medicine and drug designing. It has been shown that the traditional in silico methods of free energy calculation based on one-off molecular dynamics (MD) simulation do not produce reproducible, and hence, reliable results. Rather the ensemble (MD) simulation methodology has been proposed which overcomes this problem of non-reproducibility by substantially enhancing the sampling of phase space. Based on ensemble simulation methodology, two new methods have been developed and established, namely, Thermodynamic Integration with Enhanced Sampling (TIES) and Enhanced Sampling of Molecular dynamics with Approximation of Continuum Solvent (ESMACS) to calculate accurate, precise and reproducible binding affinity rapidly. A software toolkit, called Binding Affinity Calculator (BAC), has been developed to integrate and automate the multi-step process of simulation and analyses featured by TIES and ESMACS, which is quite tedious and prone to errors if performed manually. It constitutes a complex computational workflow comprised of many parts; these can all be done on a single multicore platform, keeping the data and compute close together so as to ensure the minimal time to solution. BAC allows one to calculate precise and reproducible binding affinity very rapidly, and hence, such predicted values can be used reliably for applications in clinical and pharma industries. BAC has already been employed for binding affinity calculations of several systems, including Abelson kinases and HIV-1 proteases to name a few.