Current computer-aided drug design methodologies in discovery of novel drug candidates for neuropsychiatric and inflammatory diseases

Abstract

Drug discovery and development is a very challenging, expensive and time-consuming process. Impressive technological advances in computer sciences and molecular biology have made it possible to use computer-aided drug design (CADD) methods in various stages of the drug discovery and development pipeline. Nowadays, CADD presents an efficacious and indispensable tool, widely used in medicinal chemistry, to lead rational drug design and synthesis of novel compounds. In this article, an overview of commonly used CADD approaches from hit identification to lead optimization was presented. Moreover, different aspects of design of multitarget ligands for neuropsychiatric and anti-inflammatory diseases were summarized. Apparently, designing multi-target directed ligands for treatment of various complex diseases may offer better efficacy, and fewer side effects. Antipsychotics that act through aminergic G protein-coupled receptors (GPCRs), especially dopamine D2 and serotonin 5-HT2A receptors, are the best option for treatment of various symptoms associated with neuropsychiatric disorders. Furthermore, multi-target directed cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors are also a successful approach to aid the discovery of new anti-inflammatory drugs with fewer side effects. Overall, employing CADD approaches in the process of rational drug design provides a great opportunity for future development, allowing rapid identification of compounds with the optimal polypharmacological profile.

Proces otkrića i razvoja lekova je veoma zahtevan, skup i dugotrajan. Veliki tehnološki napredak u molekularnoj biologiji i kompjuterskim naukama je omogućio primenu metoda kompjuterski potpomognutog dizajniranja lekova (CADD) u različitim fazama procesa otkrića i razvoja lekova. Danas CADD predstavlja efikasnu i nezamenljivu alatku, koja se široko koristi u medicinskoj hemiji za racionalni dizajn i sintezu novih jedinjenja. U ovom preglednom radu biće prikazani CADD pristupi koji se najčešće koriste od procesa identifikacije hit jedinjenja do optimizacije lead jedinjenja. Pored toga, biće predstavljeni različiti aspekti u dizajnu višeciljnih liganada za neuropsihijatrijske i inflamatorne bolesti. Pokazano je da su ova jedinjenja veoma efikasna u lečenju složenih bolesti zbog veće efikasnosti i manje neželjenih efekata koje izazivaju. Antipsihotici koji deluju preko aminergičnih G-protein spregnutih receptora (GPCR), posebno preko dopaminskih D2 i serotoninskih 5-HT2A receptora, predstavljaju najbolju opcija za lečenje različitih simptoma povezanih sa neuropsihijatrijskim poremećajima. Pored toga, dizajn i sinteza dualnih inhibitora ciklooksigenaze-2 (COX-2) i 5lipoksigenaze (5-LOX) takođe predstavlja uspešan pristup u otkrivanju novih antiinflamatornih lekova sa manje neželjenih efekata. Na kraju se može zaključiti da primena CADD metoda u procesu racionalnog dizajniranja lekova pruža značajnu priliku za dalji napredak jer omogućava brzu identifikaciju jedinjenja sa optimalnim polifarmakološkim profilom.