The medicinal chemist's dream: Faster design of better and safer drug candidates

Successful drug research depends on adequate links between therapeutic benefits for the treatment of a disease, pertinent biological targets and suitable chemical compounds. The pharmacochemistry group at EPGL is active in the development of virtual and experimental methods to enhance these links following a general hit and lead generation strategy to reduce large chemically diverse databases to lead collections. This strategy is based on a careful definition of its numerous steps and on a series of key validation processes. Particular attention is devoted to identify and improve the usefulness of virtual screening techniques widely used in drug development. The guidelines proposed here to use the best validated tools in the most suitable order will help the medicinal chemist to approach his dream, namely to be faster in the design of better and safer drug candidate

Human recombinant monoamine oxidase B as reliable and efficient enzyme source for inhibitor screening

Interest in inhibitors of monoamine oxidase type B (MAO B) has grown in recent years, due to their therapeutic potential in aging-related neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. This study is devoted to the use of human recombinant MAO B obtained from a Baculovirus expression system (Supersomes MAO B, BD Gentest, MA, USA) as reliable and efficient enzyme source for MAO B inhibitor screening. Comparison of inhibition potencies (pIC50 values) determined with human cloned and human platelet MAO B for the two series of MAO B inhibitors, coumarin and 5H-indeno[1,2-c]pyridazin-5-one derivatives, showed that the difference between pIC50 values obtained with the two enzyme sources was not significant (P>0.05, Student's t-test). Hence, recombinant enzyme is validated as convenient enzyme source for MAO B inhibitor screening

Identification of novel multifunctional compounds for the treatment of some aging related neurodegenerative diseases

Aging related neurodegenerative disorders such as Parkinson disease (PD) and Alzheimer's disease (AD) are the result of multiple pathophysiological pathways that contribute to the neurodegenerative cascade. Hence, multifunctional drug candidates able to interact with several targets are of great interest for the treatment of such diseases. Therefore, an experimental and virtual screening pathway to generate multifunctional hits showing promise for the treatment of PD or AD was suggested. Moreover, suitable experimental and virtual screening methods to rapidly test pre-focused compound libraries were developed and validated. In particular, the screening was focused on potential inhibitors of acetylcholinesterase (AChE) and monoamine oxidase B (MAO B) using a combination of in vitro enzymatic tests, docking and scoring approaches and refined molecular modeling tool

The lipophilicity behavior of three catechol-O-methyltransferase (COMT) inhibitors and simple analogues

The ionization and lipophilicity properties of the second-generation catechol-O-methyltransferase (COMT) inhibitors entacapone (1), nitecapone (2), and tolcapone (3) which share the same nitrocatechol structure but have remarkably different pharmacokinetic profiles are investigated to identify relationships between some of these physicochemical parameters and the blood-brain-barrier (BBB) passage. In addition, the lipophilicity behavior of the simpler, structurally related analogues 4-11 is studied. Combined descriptors such as Delta log P (difference between log P in two different solvent systems) and diff(log PN-1) (difference between log P of two different electrical forms of a given solute in the same system) provide insight into inter- and intramolecular interactions characteristic of the analyzed compound

Impact of species-dependent differences on screening, design, and development of MAO B inhibitors

The impact of species-dependent differences between human and rat MAO B on inhibitor screening was evidenced for two classes of compounds, coumarin and 5H-indeno[1,2-c]pyridazin-5-one derivatives. All examined compounds have shown a greater inhibitor potency toward human MAO B than toward rat MAO B. Moreover, no correlation was found between human and rat pIC(50) values. These divergences have important implications for the design and development of drugs involved in the MAO B metabolic pathway, suggesting that results obtained using rat enzyme cannot be extrapolated to human CNS, a priori. Indeed, the selection of a hit compound for lead generation could be different using human rather than rat enzyme. Moreover, the influence of substituents on the in vitro inhibition of human MAO B was markedly different between homogeneous series of coumarin and 5H-indeno[1,2-c]pyridazin-5-one derivatives, suggesting different binding modes, a hypothesis clearly supported by molecular docking simulations of inhibitors into the active site of human MAO B