Random Records

Note for the youtube lecture: Computational Drug Discovery: Machine Learning for Making Sense of Big Data in Drug Discovery Link: https://youtu.be/uoVAd_zd-90 Drug 1.        Biological entity -- biologic 2.        Chemical based drugs – synthetic drugs, natural product, small molecule Drug discovery – for one particular drug -           10-15 years -           Failure rate -- >90% -           Cost ~2 billion USD Drug discovery process (million to one compound and it could fail!!!) 1.        Identified target; ~30,000 protein (not include PTM processes) 2.        Screen for the hit compound – molecule disrupted the activity of particular protein 3.        Optimization of the hit compounds – called medicinal chemistry, scaffold hopping, bioisostere, structure-activity relationship – getting the potential compound (potent) 4.        ADMET (balance between potency and toxicity) Computational drug discovery -           Green chemistry; safe way to generate t

Note for: PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes (2017) doi: 10.1101/gad.291518.116 - Discovery of Poly(ADP-ribose) – more than 50 years - Only PARP1 has been extensively studied but not other PARPs - PARP1 has been studied in DNA damage detection and repair - Actually, PARPs have diverse range of biological roles (one of the PTMs) - Substrate for PARPs -- > protein or nucleicacid + NAD with ADP-ribose ADP-ribosylation - Reversible process which adding ADP-ribose from beta-NAD+ to protein – mono- or poly- - Catalyze the reaction called ADP-ribosylation reaction - This review focuses on o Mono(ADP-ribosylation) -- MARylation o Poly(ADP-ribosylation) -- PARylation o At amino acid site – glutamate, aspartate, and lysine residues PARPs - Writers of ADP-ribose Accessory proteins - Readers – contain ADP-ribose-binding domains (ARBD) Erasers - ADP-ribose and PAR hydrolases Feeders - Providing NAD+ (NAD+ s

Note for: Potential Strategies to Target Protein-Protein Interactions in the DNA Damage Response and Repair (DDR) Pathways doi: 10.1021/acs.jmedchem.7b00358 This paper focus on protein-protein interaction of protein in DNA damage response and repair pathways. 1.        How to select the target PPI site base on its function 2.        Functional rational and biochemical feasibility to identify a PPI inhibitor 26 PPI discuss in this paper – include BER, MMR, NER, NHEJ, HR, TLS and ICL Why focusing on PPI in DDR -         Targeting protein in DDR is not easy --> many DDR proteins are unconventional drug targets (example of conventional drug target – cell surface -- G-protein coupled receptor, ion-channel or conventional enzyme – protease/kinase) -         Drawback for DDR – assay is difficult for screening -         Some important mlcs in DDR are large – difficult to handle (purify as large scale screening) -         Instability of DDR enzymes – make it more difficul