Title: Molecular modelling and design of a novel nitrogen containing mutant p53 inhibitor having potential to restore its beneficial wild type function

Abstract:

Cancer is one of the world’s leading diseases, causing 9-10 million global deaths as per WHO (World Health organization) data in 2018. One of the major reasons of cancer is mutation in cellular guardian protein P53, whose mutation endows it with loss of function due to loss of its prime important tertiary structure. 50% of cancer cases are basically registered with P53 mutation either somatic or germline. To address this, one novel strategy has been investigated over the last few years is to restore P53 function by restoring its tertiary structure and interaction dynamics via interaction with novel organic ligands. In pursuance, we have a designed a novel nitrogen based heterocyclic ligand which can restore mutant P53 function, especially focussing on Y220C, an aberrant mutation found in breast cancer cells. Interestingly the ligand revealed interactions with the most hotspot zones of P53 that is residue 121-185, residue 242-250 and residue 275-282 insinuating its broad spectrum of action. The ligand was designed by de novo ligand design via fragment based joining and disjoining algorithm on the in situ ligand PK9324 (PDB ID:EYB, Protein PDB: 6GGD) using programme LEA3D. The genetic algorithm was used to create the ligands offsprings and PLANTS based docking with scoring function was used to select the best fitting ligand inside the binding site. Later, molecular dynamics simulation revealed stable seating of the ligand within the cavity together with hydrogen bonding interactions with the key amino acid residues spanning the cavity. The torsional flexibility of the ligand was supposed to be responsible for such nice seating and interaction which could restore the proximity of the S3/S4 and S7/S8 loop interactions enabling refolding potential of the protein. The cysteine residue at 220 position was seen rotated due to ligand interaction shortening the hydrophobic cavity in between which was seen after the mutation in the P53 protein. The dipole moment was restored to original indicating establishment of electrostatic interactions in between the loops which was lost after mutation. The toxicity score in silico has been encouraging by SWISS ADME and Boiled Egg diagram, a drug likeliness screening was also undertaken by Molinspiration and SWISS ADME. The recovery data was promising and altogether it suggests to be a promising anticancer ligand restoring vicious and non-functional mutant P53 into a functional wild type equivalent one.

Biography:

Souvik Basak, age 39 years, has completed his B.Pharm. and M.Pharm from Jadavpur University, Kolkata, India (2004 and 2006 respectively) and accomplished his PhD from Nanyang Technological University, Singapore at 2013. He has been working as Associate Professor, Division of Pharmaceutical Chemistry in Dr. B.C. Roy College of Pharmacy & Allied Health Sciences, Durgapur, WB, India since 2018. He has published more than 30 papers in various international journals of repute, several book chapters and more than 50 conference proceedings/presentations. He has published one Indian patent and associated as research consultant with various international research farms and Professors. He is currently also a member of fellow of Institute of Chemist, India

Title: Assay development of hight content metabolic stability and aldehyde oxidase benchmarking tool for drug discovery

Abstract:

Understanding the metabolism of new chemical entities at an early stage has become common practice in the pharmaceutical industry. An automated, high throughput, in vitro assay for evaluation of the intrinsic clearance in liver microsomes, Cytochrome P450 (CYP) contribution, and metabolic soft spot identification, was developed. This assay utilizes a combination of technologies and methods including automated liquid handling, acoustic sampling, in silico prediction, and hybrid quadrupole -orbitrap mass spectrometry, to efficiently generate and deliver data both in a high throughput manner, and in a reasonable time frame early in the drug discovery process. Aldehyde oxidase (AO) has become an important clearance pathway in recent years. Due to the subcellular location of this enzyme, first tier discovery metabolic stability assays using human liver microsomes fail to identify the contribution of AO-mediated metabolism in new chemical entities. An automated, high throughput, in vitro assay was developed as a benchmarking tool for an in vitro - in vivo correlation of intrinsic clearance using commercial drugs known to be metabolized by AO using in vitro systems (human liver cytosol, liver S-9 fractions and human hepatocytes). This work provides a relative scale that can be used for an in vitro - in vivo correlation of AO clearance and can provide acceptance criteria as to when a potential new drug candidate that is metabolized by AO will have acceptable human clearance. This assay allows for quick structure activity relationships to guide further structural modifications for new chemical entities predicted to have AO mediated metabolism.

Biography:

Marina Slavsky has completed her M.S. from Moscow State University of Fine Chemical Technologies, Russia. She is the senior scientist in AstraZeneca DMPK group. Marina has extensive experience in high throughput assay development, automation, validation, and implementation for drug discovery and development.

Title: HIPPO-YAP1: a promising new pathway for cancer therapy

Abstract:

The HIPPO signaling pathway is an evolutionary conserved pathway that has received increasing attention in cancer research over the past years. The deregulation of HIPPO kinase signaling and the subsequent activation of the YAP1 transcriptional regulator drives tumor cell proliferation, protects from therapy by promoting cell survival and signals towards a tumor permissive immune environment. In this presentation, I will speak about how to detect YAP1 activation and will present examples of tumors with high YAP1 activity and deregulated HIPPO kinase signaling. I will further give you an overview on strategies for targeting the HIPPO-YAP1 pathway in cancer therapy, including recent advancements on small molecule allosteric ligands of TEAD proteins, which are the preferred transcription factor binding partners of YAP1 and represent the most terminal effectors of the HIPPO-YAP1 signaling cascade.

Biography:

Iris Valtingojer is a group leader in the Molecular Oncology Research Department from Sanofi, France. Her professional experience lies in the leadership of small molecule drug discovery projects in a precision medicine context. Over the past 10 years she has taken multiple projects from target identification up to development candidate selection. Iris’ research team focuses on new and innovative pathways for cancer therapy and the identification of targets and drugs in this context. She joined Sanofi as a Post-Doc in Biochemistry and holds a Ph.D. from the Max-Planck Institute in Cologne, Germany, as well as a Master degree in Biology and Biochemistry from the University of Vienna, Austria.

Title: Prediction of selected biosynthetic pathways for the lipopolysaccharide components in porphyromonas gingivalis

Abstract:

Porphyromonas gingivalis is an oral human pathogen. The bacterium destroys dental tissue and is a serious health problem worldwide. Experimental data and bioinformatic analysis revealed that the pathogen produces 3 types of lipopolysaccharide (LPS): normal (O-type), anionic (A-type), and capsular (K-type). The enzymes involved in the production of all three types of lipopolysaccharide have been largely identified for the first two and partially for the 3rd type. In the current work, we use bioinformatics tools to predict biosynthetic pathways for the production of the normal (O-type) lipopolysaccharide in the W50 strain Porphyromonas gingivalis and compare the pathway with putative other pathways in fully sequenced and completed genomes of other pathogenic strains. Selected enzymes from the pathway have been modeled and putative structures are presented. The pathway for the A-type antigen could not be predicted at this time due to two mutually exclusive structures proposed in the literature. Pathway for the K-type antigen biosynthesis could not be predicted either due to the lack of structural data for the antigen. However, pathways for the synthesis of lipid A, its core components, and the O-type antigen ligase reaction have been proposed based on a combination of experimental data and bioinformatic analyses. The predicted pathways are compared with known pathways in other systems and discussed. It is the first report in the literature showing in detail predicted pathways for the synthesis of selected LPS components for the model W50 strain of P. gingivalis.

Biography:

Swietnicki is a scientist working on antibacterial strategies. The work is focused on novel vaccines and therapeutics targeting bacterial virulence systems. Dr. Swietnicki obtained his Ph.D. in Biochemistry and Molecular Biology from the University of Florida, Gainesville, FL, USA, in 1995 for his work on Hepatitis A Virus 3C protease. Later he worked on human prion proteins at CWRU, Cleveland, OH, USA before starting work on Select Agents at USAMRIID, Ft. Detrick, MD, USA, and ECBC, APG, MD, USA. In 2011 he moved to Poland to work on virulence blockers of enteropathogenic E. coli at EIT+ and later on novel vaccines against periodontitis at the Institute of Immunology and Experimental Therapy of PAS in Wroclaw, PL.

Title: Quality risk management in pharmaceutical industry

Abstract:

Recently the application of Quality Risk Management (QRM) in the pharmaceutical industry has evolved and become a mandatory regulatory requirement. QRM is a continuous process of minimizing risks to product quality throughout its life cycle in order to optimize a product’s benefits and outweigh the risks. It is a systematic process for the assessment, control, and review of risks to the quality of the pharmaceutical product. ‘Risk’ is defined as the combination of the probability of occurrence of harm and the severity of that harm. ICH Q9 Guideline, Quality Risk Management illustrates core principles and tools of quality risk management to aid in efficacious and persistent risk-based decisions to both the industries viz. Regulatory and Pharmaceutical in regard to the quality of the drug substance as well as drug product from the patient’s perspective. A few examples of QRM systems that require practical decision-making are Validation, Documentation, Training, Inspection etc. Risk ranking and filtering is one of the widely used basic tools to identify and categorize the potential threat and risk is ranked using risk descriptors such as high, medium or low. Further, a risk score can also be used to define risk descriptors in risk ranking. Usually, an initial risk assessment analysis is conducted followed by final risk assessment analysis to either confirm the low risk or confirm the reduced risk. In conclusion, effective QRM system can facilitate better risk identification and subsequent risk control to improve scientific decisions.

Biography:

Prachi V. Atre has completed her Master’s in Industrial Pharmacy Practice from St.John’s University, Queens, NY, 11439. She has 3+ years of experience in injectables and is currently working as a Formulation Scientist II at Nexus Pharmaceuticals, Inc. She has published poster abstracts and presentations at Annual Meetings and Expositions such as American Asociation of Pharmaceutical Scientists (AAPS) and Controlled Release Society (CRS). She has good written and communication skills and has published review article on injectables recently.