Can someone please explain in detail with examples to clarify me the main difference between ligand, substrate and co-factors. I am curious about it. If there is no difference then why using the different terms for Ligand and Substrate?
Anything that binds to a receptor of any kind is a ligand. Examples: a peptide hormone binding to its cell surface receptor, an allosteric effector of an enzyme, oxygen binding to hemoglobin, a substrate of an enzyme.
A substrate is acted upon catalytically by an enzyme and is converted into something else, a product, through a covalent change. Examples: charging of a tRNA with its cognate amino acid by a tRNA synthetase (there are 3 substrates in this reaction: the uncharged tRNA, the amino acid, and ATP), phosphorylation of glucose by hexokinase (the substrates are glucose and ATP), relaxation of DNA supercoils by a topoisomerase (which involves breaking and resealing of the DNA backbone), proteases (peptides or proteins are the substrate).
A cofactor is a substance that is bound either covalently or noncovalently to an enzyme and participates in the reaction but is not ultimately changed. Many vitamins are cofactors. Examples include pyridoxal phosphate, FAD, various inorganic ions. Here is a Wikipedia article about cofactors that provides a list of them
Lets try to explain these concepts with examples as you solicited:
SUBSTRATE
Example 1: CO2 + H2O are substrates for carbonic anhydrase (an enzyme) to react and produce CO3H2 (actually it would be CO3- + H+. At the same time CO3H2 is also a substrate of carbonic anhydrase to produce CO2 + H2O because carbonic anhydrase works in both senses and the reaction is reversible. Carbonic anydrase cannot be found in the end product of the reaction, but catalyzes it: make it happen.
LIGAND
Example 2: TNF (tumor necrosis factor) is a ligand of the TNFR (tumor necrosis factor receptor). There is a physical and chemical union between a ligand and its receptor that induces changes usually in the receptor and unleashes reactions in the intracellular portion of the receptor (usually dimerizatin of the receptor and phosphorylation of kinases).
COFACTOR
Example 3: The transcription of a gene needs mainly the activity of an inducer or promoter (transcription factor), and also needs RNA polimerase activity. This fundamental enzyme does not work alone, but receives the "help" of many cofactors, to carry out its job. Transcription initiation is regulated by additional proteins, known as activators and repressors, and, in some cases, associated coactivators or corepressors, which modulate formation and function of the transcription initiation complex.
Things would have got clear, ligands bind to receptor as well as other molecules but when they bind to receptor, cascade of events called signalling is produced in cell.