Polypharmacology: In Silico Methods of Ligand Design and Development

Abstract

How to design a ligand to bind multiple targets, rather than to a single target, is the focus of this review. Rational polypharmacology draws on knowledge that is both broad ranging and hierarchical. Computer-aided multitarget ligand design methods are described according to their nested knowledge level. Ligand-only and then receptor-ligand strategies are first described; followed by the metabolic network viewpoint. Subsequently strategies that view infectious diseases as multigenomic targets are discussed, and finally the disease level interpretation of medicinal therapy is considered. As yet there is no consensus on how best to proceed in designing a multitarget ligand. The current methodologies are bought together in an attempt to give a practical overview of how polypharmacology design might be best initiated.

Structure-Based Discovery of Dual-Target Hits for Acetylcholinesterase and the α7 Nicotinic Acetylcholine Receptors: In Silico Studies and In Vitro Confirmation

“…Despite the requirements of VS for high quality models of binding sites and screening databases, it has proven useful for the identification of new ligands for single targets and many methodological improvements have been made over the past decades [ 36 , 37 ]. Adding a second biological target adds another significant constraint to the problem, which is often addressed by pre-filtering or pre-screening the compound database based on one target before testing the second target [ 23 ].…”

“…A prerequisite is the availability of enough data of adequate quality in order to construct predictive models. With the number of published X-ray structures, ligand datasets, and the ever-increasing size of screening compound databases, these strategies are becoming increasingly more feasible [ 23 ]. Nevertheless, VS for multi-target-directed ligands is not as commonly used as might be expected due to the complexity of the task and a lack of established protocols [ 23 ].…”

“…A prerequisite is the availability of enough data of adequate quality in order to construct predictive models. With the number of published X-ray structures, ligand datasets, and the ever-increasing size of screening compound databases, these strategies are becoming increasingly more feasible [23].…”

“…Nevertheless, VS for multi-target-directed ligands is not as commonly used as might be expected due to the complexity of the task and a lack of established protocols [23].…”

A study of the properties, reactivity and anticancer activity of novel N-methylated-3-thiazolyl or 3-thienyl carbazoles and their Pd(II) and Pt(II) complexes

“…The development of new antitumor drugs with improved activities and lower side effects than those used nowadays in CT is still one of the main challenges of current research in medicinal chemistry. Among the variety of strategies used nowadays in drug discovery [6][7][8][9][10][11], those with greater expectations are based on: a) natural products and/or b) new synthetic products with several bioactive arrays (i.e. by incorporation of an additional bioactive unit in the backbones of commercially available pharmaceuticals or known drugs and commonly known as "molecular hybridization approach") [6][7][8][9][10][11].…”