Into the Fray! A Beginner's Guide to Medicinal Chemistry

Abstract

Modern medicinal chemistry is a complex, multidimensional discipline that operates at the interface of the chemical and biological sciences. The medicinal chemistry contribution to drug discovery is typically described in the context of the wellrecited linear progression of the drug discovery pipeline. However, compound optimization is idiosyncratic to each project, and clear definitions of hit and lead molecules and the subsequent progress along the pipeline becomes easily blurred. In addition, this description lacks insight into the entangled relationship between chemical and pharmacological properties, and thus provides limited guidance on how innovative medicinal chemistry strategies can be applied to solve optimization problems, regardless of the stage in the pipeline. Through discussion and illustrative examples, this article seeks to provide insights into the finesse of medicinal chemistry and the subtlety of balancing chemical properties pharmacology. In so doing, it aims to serve as an accessible and simple-to-digest guide for anyone who wishes to learn about the underlying principles of medicinal chemistry, in a context that has been decoupled from the pipeline description.

SwissBioisostere 2021: updated structural, bioactivity and physicochemical data delivered by a reshaped web interface

“…exchanging part of a bioactive molecule by a fragment to generate a new one, was driven by the similarity principle stating that similar molecules are prone to have similar activities ( 3 ) and demonstrated later ( 4 ). Consequently, classical bioisosterism focuses on keeping stable physicochemical properties, like size, polarity or lipophilicity ( 5 ). Modern drug discovery has made the concept evolve to the more qualitative and pragmatic notion of non-classical bioisosterism .…”

2‐Amino‐4‐aryl‐5‐oxo‐4,5‐dihydropyrano[3,2‐c]chromene‐3‐carbonitriles with Microtubule‐Disruptive, Centrosome‐Declustering, and Antiangiogenic Effects in vitro and in vivo

“…The development of new drugs is mainly based on the synthesis and screening of compound libraries, and on the elucidation of target-ligand interactions, structure-activity relationships (SAR) and target/disease selectivities. [1] When following a targetoriented strategy, one-pot multi-component reactions (MCR) are an excellent approach to the synthesis of large libraries of compounds with systematically varied substituents. [2] Prominent examples of such multi-component reactions often-used for drug development are those named after Ugi, Biginelli and Van Leusen, and modifications thereof.…”

Low-Frequency Vibrational Spectroscopy and Quantum Mechanical Simulations of the Crystalline Polymorphs of the Antiviral Drug Ribavirin

“…One important factor that directly affects the crystalline polymorphism of drug molecules is conformational flexibility or the ability of the molecules to achieve multiple three-dimensional shapes. The conformational flexibility of pharmaceutical compounds has long been a subject of study and the basis for designing and understanding drug function, generally represented as the structure–activity relationship. , The conformations of several antivirals have been studied in this context, including acyclovir, peramivir, and ritonavir, , to name a few. The conformation of ribavirin has been the subject of computational conformational analyses before, using both semiempirical , and density functional theory methods .…”