ABSTRACT
BACKGROUND Schistosomiasis is a neglected tropical disease caused by trematodes of the genus Schistosoma, with a limited treatment, mainly based on the use of praziquantel (PZQ). Currently, several aspartic proteases genes have already been identified within the genome of Schistosoma species. At least one enzyme encoded from this gene family (SmAP), named SmCD1, has been validated for the development of schistosomicidal drugs, since it has a key role in haemoglobin digestion by worms. OBJECTIVE In this work, we integrated a structure-based virtual screening campaign, enzymatic assays and adult worms ex vivo experiments aiming to discover the first classes of SmCD1 inhibitors. METHODS Initially, the 3D-structures of SmCD1, SmCD2 and SmCD3 were generated using homology modelling approach. Using these models, we prioritised 50 compounds from 20,000 compounds from ChemBridge database for further testing in adult worm aqueous extract (AWAE) and recombinant SmCD1 using enzymatic assays. FINDINGS Seven compounds were confirmed as hits and among them, two compounds representing new chemical scaffolds, named 5 and 19, had IC50 values against SmCD1 close to 100 μM while presenting binding efficiency indexes comparable to or even higher than pepstatin, a classical tight-binding peptide inhibitor of aspartyl proteases. Upon activity comparison against mammalian enzymes, compound 50 was selective and the most potent against the AWAE aspartic protease activity (IC50 = 77.7 μM). Combination of computational and experimental results indicate that compound 50 is a selective inhibitor of SmCD2. Compounds 5, 19 and 50 tested at low concentrations (10 uM) were neither cytotoxic against WSS-1 cells (48 h) nor could kill adult worms ex-vivo, although compounds 5 and 50 presented a slight decrease on female worms motility on late incubations times (48 or 72 h). MAIN CONCLUSION Overall, the inhibitors identified in this work represent promising hits for further hit-to-lead optimisation.
ABSTRACT
Abstract: Developing a novel drug is a complex, risky, expensive and time-consuming venture. It is estimated that the conventional drug discovery process ending with a new medicine ready for the market can take up to 15 years and more than a billion USD. Fortunately, this scenario has recently changed with the arrival of new approaches. Many novel technologies and methodologies have been developed to increase the efficiency of the drug discovery process, and computational methodologies have become a crucial component of many drug discovery programs. From hit identification to lead optimization, techniques such as ligand- or structure-based virtual screening are widely used in many discovery efforts. It is the case for designing potential anticancer drugs and drug candidates, where these computational approaches have had a major impact over the years and have provided fruitful insights into the field of cancer. In this paper, we review the concept of rational design presenting some of the most representative examples of molecules identified by means of it. Key principles are illustrated through case studies including specifically successful achievements in the field of anticancer drug design to demonstrate that research advances, with the aid of in silico drug design, have the potential to create novel anticancer drugs.
Resumen: El desarrollo de un nuevo fármaco es un proceso complejo y arriesgado que requiere una enorme cantidad de tiempo y dinero. Se estima que el proceso estándar para producir un nuevo fármaco, desde su descubrimiento hasta que acaba en el mercado, puede tardar hasta 15 años y tener un costo de mil millones de dólares (USD). Por fortuna, este escenario ha cambiado recientemente con la llegada de nuevas tecnologías y metodologías. Entre ellas, los métodos computacionales se han convertido en un componente determinante en muchos programas de descubrimiento de fármacos. En un esfuerzo por incrementar las posibilidades de encontrar nuevas moléculas con potencial farmacológico, se utilizan técnicas como el cribado virtual de quimiotecas construidas con base en ligandos o estructuras para la identificación de hits y hasta para la optimización de compuestos líder. En lo que respecta al diseño y descubrimiento de nuevos candidatos a fármacos contra el cáncer, estos enfoques tienen, a la fecha, un impacto importante y aportan nuevas posibilidades terapéuticas. En este artículo se revisa el concepto del diseño racional de moléculas con potencial farmacológico, ilustrando los principios clave con algunos de los ejemplos más representativos y exitosos de moléculas identificadas mediante estas aproximaciones. Se incluyen casos desarrollados en el campo del diseño de fármacos contra el cáncer con la finalidad de mostrar cómo, con la ayuda del diseño asistido por computadora, se pueden generar nuevos fármacos que den esperanza a millones de pacientes.