Abstracts

A Biofocussed Chemoprospecting Approach to Drug Discovery: Design, Synthesis and Bioactivity Screening of Diverse Biofocussed Chemical Libraries

by Balmukund Thakkar




Institution: Universitetet i Troms
Department:
Year: 2017
Keywords: VDP::Mathematics and natural science: 400::Chemistry: 440::Organic chemistry: 441; Synthesis, Peptide coupling, Cyclization, Tartaric acid bisamides, Piperazine-2,5-diones, Dipeptide esters, Tartrimides, Diversity oriented synthesis; VDP::Mathematics and natural science: 400::Chemistry: 440::Theoretical chemistry, quantum chemistry: 444; Density functional theory, Geometry optimization, Transition state search, Intrinsic reaction coordinates, Conformational search, B3LYP, DFT; VDP::Mathematics and natural science: 400::Chemistry: 440::Pharmaceutical chemistry: 448; Drug discovery, Hit-generation, Lead optimization, Bioprospecting, Chemoprospecting, Biofocussed chemoprospecting, Peptidomimetics, Cheminformatics, Computer aided drug design (CADD), Docking, Homology modelling; VDP::Matematikk og Naturvitenskap: 400::Kjemi: 440::Organisk kjemi: 441; VDP::Matematikk og Naturvitenskap: 400::Kjemi: 440::Teoretisk kjemi, kvantekjemi: 444; VDP::Matematikk og Naturvitenskap: 400::Kjemi: 440::Legemiddelkjemi: 448
Posted: 02/01/2018
Record ID: 2153078
Full text PDF: http://hdl.handle.net/10037/11155


Abstract

With pharma R & D witnessing rising cost, high attrition rates and an overall decline in productivity in recent times, newer approaches are needed for more efficient early phase drug discovery. This thesis describes a new approach, biofocussed chemoprospecting. The essence of the approach is to use diverse, yet bio-like compounds for efficient hit-finding, along with property filtering and optimization of qualities such as diversity of physicochemical properties, drug likeness, ease of synthesis and low cost for efficient selection of compounds.Three libraries based on biomolecules such as linear and cyclic dipeptides, and tartaric acid were designed. Virtual libraries were generated, and their physicochemical properties and drug likeness were analysed. The libraries of compounds with optimum diversity were synthesized, and multiple compounds with significant bioactivities were found. The substitution effects for cyclization reaction were rationalized using QM methods to enable synthetic efficiency as a parameter of library design. The overall success of the approach can be attributed essentially to the efficient library design as an outcome of focus on bio-likeness and optimized diversity the core ideas of the biofocussed chemoprospecting approach.Advisors/Committee Members: Engh, Richard (advisor).