Estudo em complexos fármaco-receptor utilizando bioquímica quântica

Abstract

The drug development process has been improved by the add of other knowledge areas in the field of pharmaceutical sciences. Among these improvements, the introduction of the computational simulation was, with no doubt, one of the greatest landmarks for the field’s development. Nowadays, there are two main targets in drug development breakthrough, namely, the G protein-coupled receptors (GPCRs) and the immunotherapeutics. 5-HT1B receptors have been targeted for the treatment of migraine, since they act in the brain arteries contraction. By the other hand, class C GPCRs are potent neuromodulators, though small attention has been dedicated to them, such as the GABAB receptors. These receptor acts as potent inhibitors of the neuronal signal, leadind to impairments in the neurotransmitters release and closure of ionic channels. Despite its pharmacological relevance, only baclofen is approved by United States-Food and Drug Administration (US-FDA) as a molecule targeting GABAB, being used to treat neuropathic pain. For the class of immunotherapeutics, the most remarkable are the monoclonal antobodies (mAtb) which impair the binding between checkpoint proteins of T cells and their ligands in cancer cells. The main target for these mAtb is the programmed cell death protein 1 (PD-1) and its ligands, PD-L1 and PD-L2. In this sense, this work propose a quantum biochemistry evaluation of the interactions made by compound thar act in 5-HT1B, PD-1 e GABAB receptors aiming to deepen the knowledge and describe the key points for the docking and stabilization of these compunds within the binding site. Thus, we take into account the crystallographic structure of the three receptors, which were fractionated in amino-acid residues by the molecular fractionation with conjugate caps (MFCC) scheme for posterior quantum (Density Functional Theory - DFT) calculation. By our results, it was possible to predict the relevance of the amino-acids that compose the binding site from the three receptors, including the residues Asp(D)129, Asp(D)352, Asp(D)123, Glu(E)198, Asp(D)204, Phe(F)330, Leu(L)126, Phe(F)351, Ile(I)130, Val(V)201, Val(V)200, Thr(T)355 e Arg(R)114, that are part of the binding site for dihydroergotamine-5-HTR complex, the residues Ser(S)130, Gly(G)151, Ser(S)153, His(H)170, Tyr(Y)250, Trp(W)278, Glu(E)349, Val(V)201, Ser(S)152, Ser(S)154, Gln(Q)348, Arg(R)168 e Trp(W)65, which compose the GABAB’s binding site for GABA, baclofen, SCH50911 and 2-hydroxysaclofen, as well as the lisine residue Lys(K)131 from PD-1 as the most relevant for the coupling of pembrolizumab, nivolumab and PD-L1. These residues shown the most intense attraction of repulsion energies, forming the key point for the ligand’s anchoring and stabilization. Through these data, it was possible to identify and describe the most important regions for ligands and receptors, as well as explain and differentiate, in a molecular and energetic level, the binding affinity experimentally found for these ligands.