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MICE-PES: An Algorithm for Accurate Conformational Analysis and its Implementation to Natural Products

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Version 2 2023-09-26, 01:35
Version 1 2021-11-23, 11:39
thesis
posted on 2023-09-26, 01:35 authored by Hashmi, Muhammad Ali

Secondary metabolites from natural sources have revolutionized the modern drug industry by acting as lead compounds. Many commercial drugs have evolved originally from natural molecules before being synthesized in the laboratory for commercialization. Because of the importance of natural molecules, it is crucial to determine their structural properties carefully as it is essential for their synthesis and studying their pharmacological behaviour. Many natural molecules have flexible structures and can adopt many different conformations in solution at room temperature. Hence, the determination of their relative configuration is a challenging task with the available experimental techniques. For structural analysis of natural molecules and to study their properties, all conformers which might be responsible for their chemical properties have to be considered.  Theoretical chemistry has been very helpful in absolute structure determination of complex and conformationally flexible natural molecules by calculating their theoretical nuclear magnetic resonance, ultraviolet, infra red, and circular dichroism spectra etc. There are a number of software tools that offer conformational analysis by utilizing different molecular mechanics approaches. They produce a large number of possible conformers and are not general purpose, thus compromising accuracy. Apart from that, different force fields available for conformational analysis and minimization have been designed for specific molecular classes and do not produce good results beyond their scope.  In the past, there have been reports about a “build-up procedure” for predicting the low energy conformations of peptides by optimising smaller fragments of the molecule under study and then joining them while minimizing their energies using force fields. Later on, this method was extended to predict the structure of DNA from sequences. This method used force field methods and did not gain much popularity due to its various limitations.  Here, MICE-PES (Method for the Incremental Construction and Exploration of the Potential Energy Surface) is presented, an algorithm which performs a conformational analysis using high level quantum chemical calculations by building the molecule incrementally from its smallest possible analogue whose conformational degrees of freedom are very well separated than the rest of the molecule. MICE-PES has been validated through studies on known biomolecule 3-epi-xestoaminol whose absolute configuration has been determined already by experimental and theoretical methods. MICE-PES has also been used to assign the relative configuration of a natural product (meroterphenol C) whose configuration could not be established experimentally. Overall, the development of MICE-PES will be very helpful in solving problems in the study of conformationally flexible systems, in all aspects of organic chemistry.

History

Copyright Date

2018-01-01

Date of Award

2018-01-01

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

CC BY-NC-SA 4.0

Degree Discipline

Chemistry

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Doctoral

Degree Name

Doctor of Philosophy

Victoria University of Wellington Unit

University Library

ANZSRC Type Of Activity code

1 PURE BASIC RESEARCH

Victoria University of Wellington Item Type

Awarded Doctoral Thesis

Language

en_NZ

Victoria University of Wellington School

School of Chemical and Physical Sciences

Advisors

Lein, Matthias; Keyzers, Robert