The binding energies and Gibbs free energies ofbinding for melatonin and other indole-,naphthalene-, and benzene-moiety ligands totrans-membrane sections of the seven-helix humanmelatonin receptor MT1 have been calculated atthe ab initio and semi-empirical levels using GAMESS, and with molecular mechanics using Sybyl. A linear relationship was found between the Sybyl-calculated binding energies and theexperimentally-determined pKi values, and alinear fit of calculated HINT scores to theexperimentally-measured ΔG values givesdeltaG = -0.00263Hscore - 9.477, in kcal/mol. In addition, the interactions between individual residues in MT1 and various ligands were examined to determine why some ligands bind more strongly to MT1 than others. The magnetic circular dichroism spectra of melatonin bound tofragments of MT1 were also calculated, in theCNDO/S-D approximation.

Anthropogenic activities have drastically altered chemical exposure, with traces of synthetic chemicals detected ubiquitously in the environment. Many of these chemicals are thought to perturb endocrine function, leading to declines in reproductive health and fertility, and increases in the incidence of cancer, metabolic disorders and diabetes. There are over 90 million unique chemicals registered under the Chemical Abstracts Service (CAS), of which only 308,000 were subject to inventory and/or regulation, in September 2013. However, as a specific aim of the EU REACH regulations, the UK is obliged to reduce the chemical safety initiatives reliance on in vivo apical endpoints, promoting the development and validation of alternative mechanistic methods. The human health cost of endocrine disrupting chemical (EDC) exposure in the EU, has been estimated at €31 billion per annum. In light of the EU incentives, this study aims to evaluate current in silico and in vitro tools for EDC screening and hazard characterisation; testing the hypothesis that in silico virtual screening accurately predicts in vitro mechanistic assays. Nuclear receptor binding interactions are the current focus of in silico and in vitro tools to predict EDC mechanisms. To the author’s knowledge, no single study has quantitatively assessed the relationship between in silico nuclear receptor binding and in vitro mechanistic assays, in a comprehensive manner. Tripos ® SYBYL software was used to develop 3D-molecular models of nuclear receptor binding domains. The ligand binding pockets of estrogen (ERα and ERβ), androgen (AR), progesterone (PR) and peroxisome proliferator activated (PPARγ) receptors were successfully modelled from X-ray crystal structures. A database of putative-EDC ligands (n= 378), were computationally ‘docked’ to the pseudo-molecular targets, as a virtual screen for nuclear receptor activity. Relative to in vitro assays, the in silico screen demonstrated a sensitivity of 94.5%. The SYBYL Surflex-Dock method surpassed the OECD Toolbox ER-Profiler, DfW and binary classification models, in correctly identifying endocrine active substances (EAS). Aiming to evaluate the current in vitro tools for endocrine MoA, standardised ERα transactivation (HeLa9903), stably transfected AR transactivation (HeLa4-11) assays in addition to novel transiently transfected reporter gene assays, predicted the mechanism and potency of test substances prioritised from the in silico results (n = 10 potential-EDCs and 10 hormone controls). In conclusion, in silico SYBYL molecular modelling and Surflex-Dock virtual screening sensitively predicted the binding of ERα/β, AR, PR and PPARγ potential EDCs, and was identified as a potentially useful regulatory tool, to support EAS hazard identification.

This thesis considers atom`s attributes, which affects shape of molecules. It describes rules that are basic for molecule creation. This text features basic attributes and rules, which affects the final shape of molecule. Next part of this text explains several ways to display molecule. Following parts of this thesis describes several ways how to store and represent atom and molecules in computer technology along with solution of these problems that are used for this thesis.